Dibenzyl amine compounds and derivatives

ABSTRACT

Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

BACKGROUND OF INVENTION

This invention relates to dibenzyl amine compounds and derivatives,pharmaceutical compositions containing such compounds and their use toelevate certain plasma lipid levels, including high density lipoprotein(HDL)-cholesterol and to lower certain other plasma lipid levels, suchas low density lipoprotein (LDL)-cholesterol and triglycerides andaccordingly to treat diseases which are affected by low levels of HDLcholesterol and/or high levels of LDL-cholesterol and triglycerides,such as atherosclerosis and cardiovascular diseases in certain mammals(i.e., those which have CETP in their plasma), including humans.

Atherosclerosis and its associated coronary artery disease (CAD) is theleading cause of mortality in the industrialized world. Despite attemptsto modify secondary risk factors (smoking, obesity, lack of exercise)and treatment of dyslipidemia with dietary modification and drugtherapy, coronary heart disease (CHD) remains the most common cause ofdeath in the U.S., where cardiovascular disease accounts for 44% of alldeaths, with 53% of these associated with atherosclerotic coronary heartdisease.

Risk for development of this condition has been shown to be stronglycorrelated with certain plasma lipid levels. While elevated LDL-C may bethe most recognized form of dyslipidemia, it is by no means the onlysignificant lipid associated contributor to CHD. Low HDL-C is also aknown risk factor for CHD (Gordon, D. J., et al., “High-densityLipoprotein Cholesterol and Cardiovascular Disease”, Circulation,(1989), 79: 8-15).

High LDL-cholesterol and triglyceride levels are positively correlated,while high levels of HDL-cholesterol are negatively correlated with therisk for developing cardiovascular diseases. Thus, dyslipidemia is not aunitary risk profile for CHD but may be comprised of one or more lipidaberrations.

Among the many factors controlling plasma levels of these diseasedependent principles, cholesteryl ester transfer protein (CETP) activityaffects all three. The role of this 70,000 dalton plasma glycoproteinfound in a number of animal species, including humans, is to transfercholesteryl ester and triglyceride between lipoprotein particles,including high density lipoproteins (HDL), low density lipoproteins(LDL), very low density lipoproteins (VLDL), and chylomicrons. The netresult of CETP activity is a lowering of HDL cholesterol and an increasein LDL cholesterol. This effect on lipoprotein profile is believed to bepro-atherogenic, especially in subjects whose lipid profile constitutesan increased risk for CHD.

No wholly satisfactory HDL-elevating therapies are on the market today.Niacin can significantly increase HDL, but has serious toleration issueswhich reduce compliance. Fibrates and the HMG CoA reductase inhibitorsraise HDL-C, but in some patients, the result is an increase of modestporportions (˜10-12%). As a result, there is an unmet medical need foran approved therapeutic agent that elevates plasma HDL levels, therebyreversing or slowing the progression of atherosclerosis.

Thus, although there are a variety of anti-atherosclerosis therapies,there is a continuing need and a continuing search in this field of artfor alternative therapies.

SUMMARY OF THE INVENTION

This invention is directed to compounds according to Formula I

or a pharmaceutically acceptable salt of said compound; wherein

A is —COO(C₁-C₄)alkyl, cyano, —CHO, —CONH₂, —CO(C₁-C₄)alkyl or Q whereinQ is a five or six membered fully saturated, partially unsaturated orfully unsaturated ring wherein each ring atom, except for the atomconnected to N of Formula I, may be replaced by a nitrogen, oxygen orsulfur atom, and wherein each ring atom may optionally be mono- ordi-substituted by oxo, cyano, a fully saturated, partially unsaturatedor fully unsaturated straight or branched chain having 1 to 6 carbonatoms, or a fully saturated, partially unsaturated or fully unsaturatedring having 3 to 8 carbon atoms, wherein each carbon atom of said chainor ring is optionally replaced by a heteroatom selected from nitrogen,oxygen or sulfur, and said carbon atom of said chain or ring isoptionally mono-, di- or tri-substituted with amino, halo, cyano,hydroxy, oxo, carboxyl, (C₁-C₆)alkoxycarbonyl, ((C₁-C₆)alkyl optionallysubstituted with one to nine halo or one or two hydroxyl),((C₁-C₆)alkoxy optionally substituted with one to nine halo or one ortwo hydroxyl), or ((C₁-C₆)alkylthio optionally substituted with one tonine halo or one or two hydroxyl), and said nitrogen atom of said chainor ring is optionally mono- or disubstituted with cyano, oxo,(C₁-C₆)alkoxycarbonyl or ((C₁-C₆)alkyl optionally substituted with oneto nine halo or one or two hydroxyl), said sulfur atom of said chain orring is substituted with one or two oxo, one to five fluorines or amino,and said chain or ring is optionally mono-, di- or trisubstituted with agroup V wherein V is a three to six membered fully saturated, partiallysaturated or fully unsaturated ring containing zero to four heteroatomsselected from nitrogen, oxygen or sulfur and optionally substituted byone to five groups selected from hydrogen, halo, cyano, hydroxy, oxo,carboxyl, (C₁-C₆)alkoxycarbonyl, ((C₁-C₆)alkyl optionally substitutedwith one to nine halo or one or two hydroxyl), ((C₁-C₆)alkoxy optionallysubstituted with one to nine halo or one or two hydroxyl), or((C₁-C₆)alkylthio optionally substituted with one to nine halo or one ortwo hydroxyl);

B is —OR¹⁷ or —S(O)_(n)R¹⁸

X is C or N, wherein if X is N, R⁴ is absent;

Y is —CR¹¹R¹²;

R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, halo,cyano, hydroxy, nitro, ((C₁-C₆)alkyl optionally substituted with one tonine halo, one or two hydroxyl, one or two (C₁-C₆)alkoxy, one or twoamino, cyano, oxo, or carboxy), ((C₁-C₆)alkoxy optionally substitutedwith one to nine halo, one or two hydroxyl, or cyano), or((C₁-C₆)alkylthio optionally substituted with one to nine halo, one ortwo hydroxyl, or cyano), or

R¹ and R² or R² and R³ are taken together to form a 5 to 7-memberedpartially unsaturated or fully unsaturated ring wherein each carbon atomof said ring is optionally replaced with an oxygen atom, wherein theoxygen atoms are not connected to each other, wherein said ring isoptionally mono-, di-, tri- or tetra-substituted with halo, andoptionally mono- or di-substituted with hydroxy, amino, nitro, cyano,oxo, carboxy, ((C₁-C₆)alkyl optionally substituted with one to ninehalo, one or two hydroxyl, one or two (C₁-C₆)alkoxy, one or two amino,one or two nitro, cyano, oxo, or carboxy), or ((C₁-C₆)alkoxy optionallysubstituted with one to nine halo, one or two hydroxyl, or cyano);

each R⁸, R⁹, R¹⁰, R¹³, and R¹⁴ are each independently hydrogen, aryl or((C₁-C₆)alkyl optionally substituted with one to nine halo);

R¹¹ and R¹² are each independently hydrogen, a fully saturated,partially unsaturated or fully unsaturated chain having 1 to 2 carbonatoms, or a fully saturated, partially unsaturated or fully unsaturatedmono- or bi-cyclic ring having 3 to 10 carbon atoms, wherein said ringis optionally bicyclic, and wherein each carbon atom of said ring isoptionally replaced by a heteroatom selected from nitrogen, oxygen orsulfur, and said carbon atom of said chain or ring is optionally mono-,di- or tri-substituted with R¹⁹, and wherein R¹¹ and R¹² are notattached to the carbon of Y at a heteroatom, and wherein R¹¹ and R¹² arenot both hydrogen, or

R¹¹ and R¹² are taken together to form a 3 to 8-membered fully saturatedor partially unsaturated mono- or bicyclic ring having optionally one tofour heteroatoms selected from oxygen, nitrogen and sulfur, wherein thering is optionally mono- di- or tri-substituted with R¹⁹;

R¹⁷ and R¹⁸ are each independently —(C₁-C₆)alkyl-NR⁸R⁹,—(C₀-C₆)alkyl-CO—NR⁸R⁹, —(C₀-C₆)alkyl-CO—OR¹⁰,—(C₁-C₆)alkyl-NR¹³—(C₀-C₆)alkyl-CO—O—R¹⁰,—(C₁-C₆)alkyl-NR¹³—(C₀-C₆)alkyl-CO—R¹⁴,—(C₁-C₆)alkyl-NR¹³—(C₀-C₆)alkyl-SO₂—R¹⁰, —(C₁-C₆)alkyl-O—CO—NR⁸R⁹,—(C₂-C₆)alkenyl-CO—O—R¹⁰, —(C₀-C₆)alkyl-aryl, —(C₀-C₆)alkyl-heteroaryl,—(C₁-C₆)alkyl-O-aryl, —(C₁-C₆)alkyl-O-heteroaryl,—(C₀-C₆)alkyl-heterocycle, —(C₀-C₆)alkyl-(C₃-C₆)cycloalkyl,—(C₀-C₆)alkyl-(C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl, (C₂-C₆)alkenyl,(C₁-C₆)alkyl, or —CO—(C₁-C₆)alkyl, wherein said R¹⁷ and R¹⁸ aryl,heteroaryl, heterocycle, cycloalkenyl, cycloalkyl, alkynyl, alkenyl, andalkyl groups are each optionally substituted independently with one tonine halo, one or two hydroxy, one to three (C₁-C₆)alkyl, one to three(C₁-C₆)haloalkyl, one to three (C₁-C₆)alkoxy, one to three(C₁-C₆)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, orcarboxy, except R¹⁷ is not aryl or heteroaryl;

each R¹⁹ is independently —(C₀-C₆)alkyl-NR⁸R⁹, —(C₀-C₆)alkyl-CO—NR⁸R⁹,—(C₀-C₆)alkyl-CO—OR¹⁰, —(C₀-C₆)alkyl-NR¹³—(C₀-C₆)alkyl-CO—O—R¹⁰,—(C₀-C₆)alkyl-NR¹³—(C₀-C₆)alkyl-CO—R¹⁴,—(C₀-C₆)alkyl-NR¹³—(C₀-C₆)alkyl-SO₂—R¹⁰, —(C₀-C₆)alkyl-O—CO—NR⁸R⁹,—O—(C₁-C₆)alkyl-CO—O—R¹⁰, —(C₂-C₆)alkenyl-CO—O—R¹⁰, —(C₀-C₆)alkyl-aryl,—(C₀-C₆)alkyl-heteroaryl, —O—(C₀-C₆)alkyl-aryl,—O—(C₀-C₆)alkyl-heteroaryl, —(C₀-C₆)alkyl-O-aryl,—(C₀-C₆)alkyl-O-heteroaryl, —(C₀-C₆)alkyl-heterocycle,—O—(C₀-C₆)alkyl-heterocycle, —(C₀-C₆)alkyl-(C₃-C₆)cycloalkyl,—O—(C₀-C₆)alkyl-(C₃-C₆)cycloalkyl, —(C₀-C₆)alkyl-(C₃-C₆)cycloalkenyl,halo, (C₂-C₆)alkynyl, (C₂-C₆)alkenyl, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, nitro, cyano, oxo, or—CO—(C₁-C₆)alkyl, wherein said aryl, heteroaryl, heterocycle,cycloalkenyl, cycloalkyl, alkynyl, alkenyl, alkyl and alkoxy groups areeach optionally substituted independently with one to nine halo, one ortwo hydroxy, one to three (C₁-C₆)alkyl, one to three (C₁-C₆)haloalkyl,one to three (C₁-C₆)alkoxy, one to three (C₁-C₆)haloalkoxy, one or twoamino, one or two nitro, cyano, oxo, or carboxy; and

n is 0, 1 or 2.

In addition, the present invention provides pharmaceutical compositionswhich comprise a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable form of saidcompound and a pharmaceutically acceptable vehicle, diluent or carrier.

In addition, the present invention provides pharmaceutical compositionsfor the treatment of atherosclerosis, coronary artery disease, coronaryheart disease, coronary vascular disease, peripheral vascular disease,dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia or myocardial infarction in a mammal whichcomprise a therapeutically effective amount of a compound of the presentinvention, or a pharmaceutically acceptable form of said compound and apharmaceutically acceptable vehicle, diluent or carrier.

Moreover, the present invention provides pharmaceutical combinationcompositions comprising: a therapeutically effective amount of acomposition comprising

a first compound, said first compound being a compound of the presentinvention, or a pharmaceutically acceptable form of said compound;

a second compound, said second compound being an HMG CoA reductaseinhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bileacid reuptake inhibitor, a cholesterol absorption inhibitor, acholesterol synthesis inhibitor, a fibrate, niacin, an antihypertensive,a combination of niacin and lovastatin, an ion-exchange resin, anantioxidant, an ACAT inhibitor or a bile acid sequestrant (preferably anHMG-CoA reductase inhibitor, a PPAR modulator, fenofibrate, gemfibrozil,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rivastatin, rosuvastatin or pitavastatin); and

a pharmaceutical vehicle, diluent or carrier. This composition may beused to treat the aforementioned diseases, including atherosclerosis.

Also, the present invention provides a kit for achieving a therapeuticeffect in a mammal comprising packaged in association a firsttherapeutic agent comprising a therapeutically effective amount of acompound of the present invention, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug anda pharmaceutically acceptable carrier, a second therapeutic agentcomprising a therapeutically effective amount of an HMG CoA reductaseinhibitor, a PPAR modulator, a cholesterol absorption inhibitor, acholesterol synthesis inhibitor, a fibrate, niacin, a combination ofniacin and lovastatin, an ion-exchange resin, an antioxidant, an ACATinhibitor or a bile acid sequestrant and a pharmaceutically acceptablecarrier and directions for administration of said first and secondagents to achieve the therapeutic effect.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of exemplary embodiments of the inventionand the examples included therein.

Before the present compounds, compositions and methods are disclosed anddescribed, it is to be understood that this invention is not limited tospecific synthetic methods of making that may of course vary. It is alsoto be understood that the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the present invention. The acidswhich are used to prepare the pharmaceutically acceptable acid additionsalts of the aforementioned base compounds of this invention are thosewhich form non-toxic acid addition salts, (i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The invention also relates to base addition salts of the compounds ofthe present invention. The chemical bases that may be used as reagentsto prepare pharmaceutically acceptable base salts of those compounds ofthe present invention that are acidic in nature are those that formnon-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (e.g.,potassium and sodium) and alkaline earth metal cations (e.g., calciumand magnesium), ammonium or water-soluble amine addition salts such asN-methylglucamine-(meglumine), and the lower alkanolammonium and otherbase salts of pharmaceutically acceptable organic amines.

The chemist of ordinary skill will recognize that certain compounds ofthis invention will contain one or more atoms which may be in aparticular stereochemical or geometric configuration, giving rise tostereoisomers and configurational isomers. All such isomers and mixturesthereof are included in this invention. Hydrates and solvates of thecompounds of this invention are also included.

Where the compounds of the present invention possess two or morestereogenic centers and the absolute or relative stereochemistry isgiven in the name, the designations R and S refer respectively to eachstereogenic center in ascending numerical order (1, 2, 3, etc.)according to the conventional IUPAC number schemes for each molecule.Where the compounds of the present invention possess one or morestereogenic centers and no stereochemistry is given in the name orstructure, it is understood that the name or structure is intended toencompass all forms of the compound, including the racemic form.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof. The term “cis” refersto the orientation of two substituents with reference to each other andthe plane of the ring (either both “up” or both “down”). Analogously,the term “trans” refers to the orientation of two substituents withreference to each other and the plane of the ring (the substituentsbeing on opposite sides of the ring).

This invention also includes isotopically-labeled compounds, which areidentical to those described by formula I, except for the fact that oneor more atoms are replaced by one or more atoms having specific atomicmass or mass numbers. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, sulfur, fluorine, and chlorine such as ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ¹⁸F, and ³⁶Cl respectively. Compounds of the presentinvention, prodrugs thereof, and pharmaceutically acceptable salts ofthe compounds or of the prodrugs which contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically-labeled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated (i.e., ³H), and carbon-14 (i.e., ¹⁴C),isotopes are particularly preferred for their ease of preparation anddelectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H), can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements and, hence, may bepreferred in some circumstances. Isotopically labeled compounds of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the schemes and/or in the Examples below, bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

In this specification and in the claims that follow, reference will bemade to a number of terms that shall be defined to have the followingmeanings:

As used herein in the specification, “a” or “an” may mean one or more.As used herein in the claim(s), when used in conjunction with the word“comprising”, the words “a” or “an” may mean one or more than one. Asused herein “another” may mean at least a second or more.

The term “about” refers to a relative term denoting an approximation ofplus or minus 10% of the nominal value it refers, in one embodiment, toplus or minus 5%, in another embodiment, to plus or minus 2%. For thefield of this disclosure, this level of approximation is appropriateunless the value is specifically stated require a tighter range.

As used herein, the term mammals is meant to refer to all mammals whichcontain CETP in their plasma, for example, rabbits and primates such asmonkeys and humans, including males and females. Certain other mammalse.g., dogs, cats, cattle, goats, sheep and horses do not contain CETP intheir plasma and so are not included herein.

The term “treating”, “treat” or “treatment” as used herein includespreventative (e.g., prophylactic) and palliative treatment.

By “pharmaceutically acceptable” is meant the carrier, diluent,excipients, and/or salt must be compatible with the other ingredients ofthe formulation, and not deleterious to the recipient thereof.

“Compounds” when used herein includes any pharmaceutically acceptablederivative or variation, including conformational isomers (e.g., cis andtrans isomers) and all optical isomers (e.g., enantiomers anddiastereomers), racemic, diastereomeric and other mixtures of suchisomers, as well as solvates, hydrates, isomorphs, polymorphs,tautomers, esters, salt forms, and prodrugs. By “tautomers” is meantchemical compounds that may exist in two or more forms of differentstructure (isomers) in equilibrium, the forms differing, usually, in theposition of a hydrogen atom. Various types of tautomerism can occur,including keto-enol, ring-chain and ring-ring tautomerism. Theexpression “prodrug” refers to compounds that are drug precursors whichfollowing administration, release the drug in vivo via some chemical orphysiological process (e.g., a prodrug on being brought to thephysiological pH or through enzyme action is converted to the desireddrug form). Exemplary prodrugs upon cleavage release the correspondingfree acid, and such hydrolyzable ester-forming residues of the compoundsof the present invention include but are not limited to those having acarboxyl moiety wherein the free hydrogen is replaced by (C₁-C₄)alkyl,(C₂-C₇)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbonatoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

The following paragraphs describe exemplary ring(s) for the generic ringdescriptions contained herein.

By “halo” or “halogen” is meant chloro, bromo, iodo, or fluoro.

By “alkyl” is meant straight chain saturated hydrocarbon or branchedchain saturated hydrocarbon. Exemplary of such alkyl groups (assumingthe designated length encompasses the particular example) are methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, isobutyl,pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.

“Alkenyl” referred to herein may be linear or branched, and they mayalso be cyclic (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl) orbicyclic or contain cyclic groups. They contain 1-3 carbon-carbon doublebonds, which can be cis or trans.

By “alkoxy” is meant straight chain saturated alkyl or branched chainsaturated alkyl bonded through an oxy. Exemplary of such alkoxy groups(assuming the designated length encompasses the particular example) aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiarybutoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy,isohexoxy, heptoxy and octoxy.

The term “aryl” means a carbocyclic aromatic system containing one, twoor three rings wherein such rings may be fused. If the rings are fused,one of the rings must be fully unsaturated and the fused ring(s) may befully saturated, partially unsaturated or fully unsaturated. The term“fused” means that a second ring is present (ie, attached or formed) byhaving two adjacent atoms in common (ie, shared) with the first ring.The term “fused” is equivalent to the term “condensed”. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

The term “heteroaryl” means a carbocyclic aromatic system containingone, two, three or four heteroatoms selected independently from oxygen,nitrogen and sulfur and having one, two or three rings wherein suchrings may be fused. The term “fused” means that a second ring is present(ie, attached or formed) by having two adjacent atoms in common (ie,shared) with the first ring. The term “fused” is equivalent to the term“condensed”. The term “heteroaryl” embraces aromatic radicals such asquinolinyl, benzofuranyl, benzodioxanyl, piprazinyl, pyridinyl,isoxazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,isoxazolyl, pyrazolyl, thiazolyl and thiadiazolyl.

The term “heterocycle” means a nonaromatic carbocyclic system containingone, two, three or four heteroatoms selected independently from oxygen,nitrogen and sulfur and having one, two or three rings wherein suchrings may be fused, wherein fused is defined above. The term“heterocycle” includes but is not limited to lactones, lactams, cyclicethers and cyclic amines, including the following exemplary ringsystems: epoxide, tetrahydrofuran, tetrahydropyran, dioxane, aziridines,pyrrolidine, piperidine, and morpholine.

It is to be understood that if a carbocyclic or heterocyclic moiety maybe bonded or otherwise attached to a designated substrate throughdiffering ring atoms without denoting a specific point of attachment,then all possible points are intended, whether through a carbon atom or,for example, a trivalent nitrogen atom. For example, the term “pyridyl”means 2-, 3- or 4-pyridyl, the term “thienyl” means 2- or 3-thienyl, andso forth.

As used herein, the expressions “reaction-inert solvent” and “inertsolvent” refer to a solvent or a mixture thereof which does not interactwith starting materials, reagents, intermediates or products in a mannerwhich adversely affects the yield of the desired product.

In one embodiment of the compounds of the present invention, X is C.

In another embodiment, A is —COO(C₁-C₄)alkyl, —CO(C₁-C₄)alkyl or Qwherein Q is a five or six membered fully unsaturated ring wherein eachring atom, except for the atom connected to N of Formula I, may bereplaced by a nitrogen, oxygen or sulfur atom, and wherein each ringatom may optionally be substituted by cyano, a fully saturated,partially unsaturated or fully unsaturated straight or branched chainhaving 1 to 6 carbon atoms, or a fully saturated, partially unsaturatedor fully unsaturated ring having 3 to 8 carbon atoms, wherein eachcarbon atom of said chain or ring is optionally replaced by a heteroatomselected from nitrogen, oxygen or sulfur, and said carbon atom of saidchain or ring is optionally mono-, di- or tri-substituted with hydrogen,amino, halo, cyano, hydroxy, oxo, carboxyl, (C₁-C₆)alkoxycarbonyl, or((C₁-C₆)alkoxy optionally substituted with one to nine halo or one ortwo hydroxyl), and said nitrogen atom of said chain or ring isoptionally mono- or disubstituted with hydrogen, (C₁-C₆)alkoxycarbonylor ((C₁-C₆)alkyl optionally substituted with one to nine halo or one ortwo hydroxyl), said sulfur atom of said chain or ring is substitutedwith one or two oxo.

In another embodiment, Q is

wherein each R⁰ is independently hydrogen, ((C₁-C₃)alkyl optionallysubstituted with one to nine halo or hydroxyl), or ((C₁-C₃)alkoxyoptionally substituted with one to nine halo or hydroxyl).

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

and R⁰ is hydrogen, (C₁-C₃)alkyl optionally substituted with one to fivehalo or one or two hydroxyl, or (C₁-C₃)alkoxy optionally substitutedwith one to five halo or one or two hydroxyl.

In another embodiment, A is —COO(C₁-C₄)alkyl, —CO(C₁-C₄)alkyl or Qwherein Q is a five or six membered fully unsaturated ring wherein eachring atom, except for the atom connected to N of Formula I, may bereplaced by a nitrogen, oxygen or sulfur atom, and wherein each ringatom may optionally be substituted by cyano, a fully saturated,partially unsaturated or fully unsaturated straight or branched chainhaving 1 to 6 carbon atoms, or a fully saturated, partially unsaturatedor fully unsaturated ring having 3 to 8 carbon atoms, wherein eachcarbon atom of said chain or ring is optionally replaced by a heteroatomselected from nitrogen, oxygen or sulfur, and said carbon atom of saidchain or ring is optionally mono-, di- or tri-substituted with hydrogen,amino, halo, cyano, hydroxy, oxo, carboxyl, (C₁-C₆)alkoxycarbonyl, or((C₁-C₆)alkoxy optionally substituted with one to nine halo or one ortwo hydroxyl), and said nitrogen atom of said chain or ring isoptionally mono- or disubstituted with hydrogen, (C₁-C₆)alkoxycarbonylor ((C₁-C₆)alkyl optionally substituted with one to nine halo or one ortwo hydroxyl), said sulfur atom of said chain or ring is substitutedwith one or two oxo; R¹ and R⁶ are each hydrogen; R⁴ is absent or ishydrogen; R¹¹ is not hydrogen; R¹² is hydrogen; and R², R³, R⁵, and R⁷are each independently hydrogen, cyano, ((C₁-C₆)alkyl optionallysubstituted with one to nine fluorines) or ((C₁-C₆)alkoxy optionallysubstituted with one to nine fluorines).

In another embodiment, X is C; and R², R³, R⁵, and R⁷ are each hydrogen,methyl, cyano, or CF₃

In another embodiment, X is C; R¹, R⁴ and R⁶ are each hydrogen; R², R³,R⁵, and R⁷ are each hydrogen, methyl, cyano, or CF₃ and A is —COOCH₂CH₃,—COOCH₃, —COCH₂CH₃, —COCH₃, or Q wherein Q is triazolyl, tetrazolyl,oxadiazolyl, isoxazolyl, or pyrazolyl, and wherein Q is optionallysubstituted with halo, ((C₁-C₆)alkyl optionally substituted with one ortwo oxo, one or two hydroxyl or one to nine halo), hydroxy,((C₁-C₆)alkoxy optionally substituted with one or two oxo, one or twohydroxyl or one to nine halo), cyano, oxo, carboxy, or(C₁-C₆)alkyloxycarbonyl.

In another embodiment, Q is

wherein each R⁰ is independently hydrogen, halo, ((C₁-C₁₀)alkyloptionally substituted with one or two oxo, one or two hydroxyl and oneto nine halo), hydroxy, ((C₁-C₆)alkoxy optionally substituted with oneor two oxo, one or two hydroxyl and one to nine halo), amino, amido,cyano, carboxy, or ((C₁-C₆)alkyloxycarbonyl optionally substituted withone or two oxo, one or two hydroxyl and one to nine halo).

In another embodiment, Q is

and R⁰ is hydrogen, (C₁-C₃)alkyl optionally substituted with one to fivehalo or one or two hydroxyl, or (C₁-C₃)alkoxy optionally substitutedwith one to five halo or one or two hydroxyl.

In another embodiment, B is —OR¹⁷ or —SR¹⁸ wherein R¹⁷ and R¹⁸ are eachindependently —(C₁-C₆)alkyl-NR⁸R⁹, —(C₀-C₆)alkyl-CO—NR⁸R⁹,—(C₀-C₆)alkyl-CO—OR¹⁰, —(C₁-C₆)alkyl-NR¹³—(C₀-C₆)alkyl-CO—O—R¹⁰,—(C₁-C₆)alkyl-NR¹³—(C₀-C₆)alkyl-NR¹³—(C₀-C₆)alkyl-SO₂—R¹⁰,—(C₁-C₆)alkyl-O—CO—NR⁸R⁹, —(C₂-C₆)alkenyl-CO—O—R¹⁰, —(C₀-C₆)alkyl-aryl,—(C₀-C₆)alkyl-heteroaryl, —(C₁-C₆)alkyl-O-aryl,—(C₁-C₆)alkyl-O-heteroaryl, —(C₀-C₆)alkyl-heterocycle,—(C₀-C₆)alkyl-(C₃-C₆)cycloalkyl, —(C₀-C₆)alkyl-(C₃-C₆)alkenyl,(C₂-C₆)alkynyl, (C₂-C₆)alkenyl, (C₁-C₆)alkyl, cyano, or—CO—(C₁-C₆)alkyl, wherein said aryl, heteroaryl, heterocycle,cycloalkenyl, cycloalkyl, alkynyl, alkenyl, and alkyl substituents areeach optionally substituted independently with one to nine halo, one ortwo hydroxy, one or two (C₁-C₆)alkoxy, one or two (C₁-C₆)alkyl, one ortwo amino, one or two nitro, cyano, oxo, or carboxy, except R¹⁷ is notaryl or heteroaryl.

In another embodiment, B is —OR¹⁷ and R¹⁷ is —(C₁-C₆)alkyl-aryl,—(C₁-C₆)alkyl-heteroaryl, —(C₀-C₆)alkyl-heterocycle,—(C₀-C₆)alkyl-(C₃-C₆)cycloalkyl, (C₁-C₆)alkyl, wherein said aryl,heteroaryl, heterocycle, cycloalkyl, and alkyl substituents are eachoptionally substituted independently with one to nine halo, one or twohydroxy, one to three (C₁-C₆)alkyl, one to three (C₁-C₆)haloalkyl, oneto three (C₁-C₆)alkoxy, one to three (C₁-C₆)haloalkoxy, one or twoamino, one or two nitro, cyano, oxo, or carboxy.

In another embodiment, R¹¹ is optionally mono- or di-substituted withR¹⁹ and R¹⁹ is —(C₀-C₆)alkyl-aryl, —(C₀-C₆)alkyl-heteroaryl,—(C₀-C₆)alkyl-heterocycle, —(C₀-C₆)alkyl-(C₃-C₆)cycloalkyl, halo,(C₂-C₆)alkynyl, (C₂-C₆)alkenyl, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,nitro, cyano, oxo, or —CO—(C₁-C₆)alkyl, wherein said aryl, heteroaryl,heterocycle, cycloalkenyl, cycloalkyl, alkynyl, alkenyl, alkyl andalkoxy groups are each optionally substituted independently with one tonine halo, one or two hydroxy, one to three (C₁-C₆alkyl, one to three(C₁-C₆)haloalkyl, one to three (C₁-C₆)alkoxy, one to three(C₁-C₆)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, orcarboxy.

In another embodiment R¹¹ and R¹² are taken together to form a 3 to8-membered fully saturated or partially unsaturated mono- or bi-cyclicring having optionally one to four heteroatoms selected from oxygen,nitrogen and sulfur, wherein the ring is optionally mono- di- ortri-substituted with R¹⁹.

In one embodiment of the method of the present invention,atherosclerosis is treated.

In another embodiment of the method of the present invention, peripheralvascular disease is treated.

In another embodiment of the method of the present invention,dyslipidemia is treated.

In another embodiment of the method of the present invention,hyperbetalipoproteinemia is treated.

In another embodiment of the method of the present invention,hypoalphalipoproteinemia is treated.

In another embodiment of the method of the present invention,familial-hypercholesterolemia is treated.

In another embodiment of the method of the present invention, coronaryartery disease is treated.

In another embodiment of the method of the present invention, myocardialinfarction is treated.

In one embodiment of the combination or kit of the present invention,the second compound is an HMG-CoA reductase inhibitor or a PPARmodulator.

In another embodiment of the combination or kit of the presentinvention, the second compound is fenofibrate, gemfibrozil, lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin,rosuvastatin or pitavastatin.

In another embodiment of the combination or kit of the presentinvention, the combination further comprising a cholesterol absorptioninhibitor, wherein the cholesterol absorption inhibitor may beezetimibe.

In general, the compounds of this invention can be made by processeswhich include processes analogous to those known in the chemical arts,particularly in light of the description contained herein. Certainprocesses for the manufacture of the compounds of this invention areprovided as further features of the invention and are illustrated by thefollowing reaction schemes. Other processes may be described in theexperimental section.

Analogous processes are disclosed in the following U.S. patents, whichare hereby incorporated by reference herein in their entirety for allpurposes: U.S. Pat. No. 6,140,342; U.S. Pat. No. 6,362,198; U.S. Pat.No. 6,147,090; U.S. Pat. No. 6,395,751; U.S. Pat. No. 6,147,089; U.S.Pat. No. 6,310,075; U.S. Pat. No. 6,197,786; U.S. Pat. No. 6,140,343;U.S. Pat. No. 6,489,478; and International Publication No. WO 00/17164and International Patent Application No. PCT/IB2005/003500.

The Reaction Schemes herein described are intended to provide a generaldescription of the methodology employed in the preparation of many ofthe Examples given. However, it will be evident from the detaileddescriptions given in the Experimental section that the modes ofpreparation employed extend further than the general proceduresdescribed herein. In particular, it is noted that the compounds preparedaccording to these Schemes may be modified further to provide newExamples within the scope of this invention. For example, an esterfunctionality may be reacted further using procedures well known tothose skilled in the art to give another ester, an amide, a carbinol ora ketone.

According to reaction Scheme 1, Hal is a halogen, and X, R¹, R², R³, andR⁴ are as described above. The desired intermediate compounds ofFormulas 4, 6 and 7 may be prepared from compounds of Formulas 1, 2 and5. Compounds of Formulas 2 and 6 may be prepared from compounds ofFormula 1 by methods known to those skilled in the art such as bydirected metallation chemistry and trapping with a suitable electrophilesuch as carbon dioxide, dimethyl formamide (DMF), or N-formylmorpholine.

More specifically, treatment of compounds of Formula 1 with1-lithium-2,2,6,6-tetramethylpiperidine and quenching with carbondioxide (F. Mongin, O. Desponds, M. Schlosser Tetrahedron Letters, 1996,37, 2767-2770) or dimethylformamide at low temperature, preferablybetween −100° C. and −78° C., in a reaction inert solvent such as etheror tetrahydrofuran (THF), preferably THF at −100° C., yields compoundsof Formulas 2 and 6 respectively. Alternatively, the compound of Formula2 may be prepared by acidic or basic hydrolysis of a compound of Formula5, for example with a suitable acid such as sulphuric acid. The compoundof Formula 6 may also be prepared from the Formula 5 compounds bypartial reduction, for example with an aluminum hydride reagent such asdiisobutylaluminum hydride (DIBAL) in a suitable reaction inert solventsuch as THF at a temperature between −78° C. and 25° C.

As shown in Scheme 1, compounds of Formula 3 may be prepared byreduction of the compounds of Formula 2 with a suitable reducing agentsuch as lithium aluminium hydride (LAH), or borane-tetrahydrofurancomplex in a reaction inert solvent such as dioxan, diethyl ether orTHF. A preferred reducing agent for reduction of compounds of Formula 2is borane-tetrahydrofuran complex, and the preferred solvent THF at atemperature between −78 and 100° C. preferably at 0-50° C.Alternatively, compounds of Formula 6 may be reduced to compounds ofFormula 3 using sodium borohydride for which the preferred solvent isethanol at a temperature between 0 and 100° C., preferably 0-50° C.

As shown in Scheme 1, compounds of Formula 4 may be prepared by reactingcompounds of Formula 3 using a suitable reagent such as phosphorustribromide or a combination of carbon tetrabromide andtriphenylphosphine in a reaction inert solvent such as methylenechloride, THF, or dioxan. The preferred reagent is a combination ofcarbon tetrabromide and triphenylphosphine, and the preferred solvent ismethylene chloride at a temperature between −78° C. and 100° C.,preferably −10° C.-20° C.

As shown in Scheme 1, compounds of Formula 7 may be prepared byreduction of compounds of Formula 5 using a suitable reducing agent suchas LAH, or in the specific case when Hal is F or Cl, by hydrogenation inthe presence of a suitable hydrogenation catalyst such as palladium oncarbon or palladium hydroxide in a reaction inert solvent such asmethanol, ethanol or acetic acid. One reducing agent of choice is LAH ina suitable solvent such as THF, methylene chloride, or dioxan. Onesolvent of choice is THF at a temperature between −78° C. and 68° C.,preferably −78° C.-40° C.

According to reaction Scheme 2, Hal is a halogen and A, X, R¹, R², R³,R⁴, R⁵, R⁶, R⁷ R¹¹, and R¹² are as described above. The desiredcompounds depicted as Formula 15 in Scheme 2, may be prepared byalkylation of compounds of Formula 10 and compounds of Formula 4 with asuitable base such as sodium hydride, potassium-tert-butoxide orpotassium hexamethyldisilazine in a suitable polar solvent such as THF,dimethylformamide, or N-methylpyrrolidinone. The base of choice ispotassium-tert-butoxide, and the preferred solvent is THF at atemperature between 0° C. and 67° C., preferably 20° C.-67° C.

Compounds of Formula 10 may be prepared by reductive amination ofcompounds of aldehydes of Formula 8 with amines of Formula 9 and asuitable reducing agent such as sodium borohydride, sodiumtriacetoxyborohydride, or sodium cyanoborohydride, in a suitable solventsuch as THF, methylene chloride, dioxan, or toluene. The method ofchoice is imine formation in the presence of 4 Å molecular sieves intoluene at a temperature between 20° C. and 111° C., preferably 100°C.-111° C., followed by removal of the solvent, dissolution of theresidue in a polar solvent, preferably ethanol, then reduction of theimine with a suitable hydride reducing agent, preferably sodiumborohydride, at a temperature between 0° C. and 78° C., preferably 20°C.-50° C.

Alternatively, compounds of Formula 15 may be prepared from compounds ofFormula 13 by a variety of methods well known to those skilled in thearts. For example in the case where A is an optionally substitutedaromatic ring it is often possible to use the appropriate halogenderivative of A and displace the halogen with the secondary amine of theFormula 13 compound generally in the presence of a base. Frequentlythese reactions are facilitated by the use of a palladium catalyst asdescribed in U.S. Pat. No. 5,576,460; International Publication No. WO98/15515; International Publication No. WO00/02887; InternationalPublication No. WO04/052939; European Publication No. EP3009560.8; andEuropean Publication No. EP99933785.0; all of which are incorporatedherein in their entireties for all purposes. In another example when Ais an optionally substituted 2-pyridyl, 2- or 4-pyrimidinyl or2-pyrazinyl group, this reaction can be achieved without the use of acatalyst by use of the corresponding 2-halopyridine, 2- or4-halopyrimidine or 2-pyrazine respectively in a suitable reaction inertsolvent such as dimethylformamide (DMF), N-methylpyrrolidinone orN,N,N′,N′-tetramethylurea using a suitable base such as triethylamine,diisopropylethylamine, potassium carbonate, or sodium carbonate. Apreferred base is diisopropylethylamine in a suitable inert solvent suchas THF, methylene chloride, or dioxan. A preferred solvent is dioxane ata temperature between −40° C. and 160° C., preferably 20° C.-140° C.

In another aspect of this invention the compounds of Formula 15 may beprepared from compounds of Formula 13 by a series of reactions, whichare well known to those skilled in the art, during which the A ring isconstructed de novo. Preferred examples of such processes include, butare not limited to, the reaction of the Formula 13 compounds with acyanating agent such as cyanogen bromide or N-cyanoimidazole to producea cyanamide intermediate. This may be further reacted with an azidesource such as sodium azide, tri-n-butyltin azide or trimethylsilylazideto produce a tetrazole. Said tetrazole may be further reacted ifdesired, for example by alkylation. In another aspect, the saidcyanamide intermediate may be reacted with hydroxylamine followed by analkanoylating agent such as an acyl chloride to produce an oxadiazolecompound (Ried, W and Eichhorn, T. A., Archiv der Pharmazie 1998,321(9), 527). In yet another aspect, the said cyanamide intermediate maybe reacted with an acylhydrazide to produce a triazole ring-containingcompound (Ried, W and Eichhorn, T. A., Archiv der Pharmazie 1998,321(9), 527).

In yet another alternative compounds of Formula 15 may be prepared byalkylation of compounds of Formula 21 with an alkyl halide of Formula 12using a suitable base such as triethylamine, diisopropylethylamine,potassium carbonate, sodium hydride or potassium tert-butoxide,preferably potassium tert-butoxide in a suitable reaction inert solventsuch as THF, methylene chloride or dioxane, preferably THF, at atemperature between −40° C. and 40° C., preferably 0-30° C.

Compounds of Formula 21 may be prepared by reductive amination ofaldehydes of Formula 6 with amines of Formula 9 and a suitable reducingagent such as sodium borohydride, sodium triacetoxyborohydride, orsodium cyanoborohydride, in a suitable solvent such as THF, methylenechloride, dioxane or toluene. The reaction proceeds via formation of animine which may be facilitated by a dehydrating agent such as 4 Åmolecular sieves in toluene at a temperature between 20° C. and 111° C.,preferably 100° C.-111° C., followed by removal of the solvent.Alternatively a titanium compound, preferably titanium tetraisopropoxidemay be employed, preferably in the absence of a solvent at roomtemperature. The imine is then reduced in a suitable polar solvent,preferably ethanol, with a suitable hydride reducing agent, preferablysodium borohydride, at a temperature between 0° C. and 80° C.,preferably 20° C.-50° C.

Compounds of Formula 13 may be prepared by reductive amination ofcompounds of Formula 6 and compounds of Formula 11 with a suitablereducing agent such as sodium borohydride, sodium triacetoxyborohydride,or sodium cyanoborohydride. The preferable reducing agent is sodiumborohydride in a suitable solvent such as ethanol, THF, methylenechloride, dioxan, or toluene. The preferred solvent is ethanol at atemperature of −78° C. and 67° C. preferably 0-50° C.

Alternatively, compounds of Formula 13 may be prepared by alkylation ofcompounds of Formula 7 and compounds of Formula 12 using a suitable basesuch as triethylamine, diisopropylethylamine, potassium carbonate, orsodium carbonate. The preferred base is diisopropylethylamine in asuitable inert solvent such as THF, methylene chloride, or dioxan. Thepreferred solvent is methylene chloride at a temperature between −40° C.and 40° C., preferably 0-20° C.

Compounds of Formula 18 may be prepared by reduction of the nitrites ofFormula 16 with DIBAL-H in a suitable solvent such as dichloromethane ata temperature between −40° C. and 40° C., preferably −20° C.

Compounds of Formula 17 wherein R¹² is H and R¹¹ is as described abovemay be prepared from compounds of Formula 16 by addition of a suitableorganometallic reagent of the formula R¹¹M where M is typically Li,MgCl, MgBr or Mgl in a suitable reaction inert solvent such as THF,diethyl ether or toluene at a temperature between −78° C. and 100° C.,preferably −10° C. to 30° C. After hydrolytic workup the intermediateketone is treated with a suitable reducing agent such as sodiumborohydride, sodium triacetoxyborohydride or lithium aluminum hydride ina suitable reaction inert solvent to give the desired alcohol of Formula17. Preferred conditions utilize sodium borohydride in ethanol between0° C. and 40° C., preferably 20° C.

Alternatively compounds of Formula 17 may be prepared from compounds ofFormula 15 by first converting the aryl halide into an aryl metalderivative where the metal may be lithium, magnesium, boron or zincfollowed by reaction with the appropriate carbonyl compound of formulaR¹¹R¹²CO, including such carbonyl compounds in which R¹¹ and R¹² areconnected in the form of a ring. Methods for accomplishing thesereactions are well known to those skilled in the art and include metalexchange with a Grignard reagent such as isopropylmagnesium chloride ina suitable reaction inert solvent such as THF, diethyl ether or toluene,preferably THF, at a temperature between −78° C. and 40° C., preferably−10° C. to 30° C. followed by reaction with the carbonyl compoundR¹¹R¹²CO at a temperature between −78° C. and 100° C., preferably −10°C. to 30° C. Another example of suitable reaction conditions involvingactivation with a diborane such as4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolanein the presence of a palladium catalyst as described above for thepreparation of Formula 15 compounds from Formula 13 compounds. Theresultant arylboronic ester or acid may be activated toward addition tothe appropriate carbonyl compound in the presence of a rhodium catalystas described by A. Fürstner and H. Krause, Adv. Synth. Catal. 2001 (4),343.

According to reaction Scheme 3, A, n, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R¹¹, R¹², R¹⁷ and R¹⁸ are as described above. The desired Formula 20compounds may be prepared from compound 15 by reaction with metalliczinc in the presence of a cobalt salt as described by H. Fillon, C.Gosmini and J. Périchon (J. Amer. Chem. Soc., 2003, 125, 3867). The arylzinc intermediate may then be reacted with the appropriate acetal orketal of formula R¹¹R¹²C(OR¹⁷)₂ as described by E. Le Gall, C. Gosminiand M. Troupel (Tet. Lett., 2006, 47, 455) to give the ether of Formula20.

The desired ether Formula 20 compounds may also be prepared from thecorresponding alcohol of Formula 17 by an alkylation reaction well knownto those skilled in the art for example as described in L. A. Paquette(Ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley andSons, Chichester, England, 1995. In a preferred aspect of this inventionthe alcohol may be treated with a base such as sodiumhexamethyldisilazide, potassium hydride or sodium hydride, preferablysodium hydride, in a reaction inert solvent such as THF and reacted withthe appropriate alkylating agent R¹⁷L where L is a leaving group such asbromide, iodide, tosylate, triflate or tosylate to give the desiredcompound of Formula 20.

Alternatively the desired ether Formula 20 compounds may be preparedfrom the corresponding acetal of Formula 19 by reaction with anappropriate organometallic compound represented by R¹¹M where M ispreferably ZnHal, in a reaction inert solvent such as THF at atemperature between −10° C. and 60° C. The preparation of the R¹¹ ZnHalreagents from the R¹¹Hal compound by treatment with metallic zinc iswell known to those skilled in the art for example as described in G.Wilkinson (Ed), Comprehensive Organometallic Chemistry, Pergamon,Oxford, 1982.

The desired acetals of Formula 19 may be prepared from the correspondingaldehyde of Formula 18 by reaction with the alcohol R¹⁷OH in thepresence of a dehydrating agent such as molecular sieves or titaniumtetrachloride. Preferred conditions for this reaction are described byA. Clerici, N. Pastori and O. Porta (Tetrahedron Letters, 1998, 54,15679).

The desired Formula 21 compounds wherein A, X, R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R¹¹, R¹² and R¹⁸ are described above, may also be prepared from thecorresponding alcohol of Formula 17 by conversion of the alcohol to aleaving group such as a mesylate, tosylate, triflate, chloride orbromide by standard procedures known to those skilled in the art. Forexample a bromide may be prepared by reacting compounds of Formula 17using a suitable reagent such as phosphorus tribromide or a combinationof carbon tetrabromide and triphenylphosphine in a reaction inertsolvent such as methylene chloride, THF, or dioxan. The preferredreagent is a combination of carbon tetrabromide and triphenylphosphine,and the preferred solvent is methylene chloride at a temperature between−78° C. and 100° C., preferably −10° C. to 30° C. This intermediate isthen reacted with the appropriate thiolate R¹⁸SM where M is preferablysodium or potassium to give the desired compound of Formula 21.Alternatively the intermediate may be converted to a thiol ether byreaction with sodium hydrosulfide or by reaction with sodium, potassiumor ammonium thiolacetate followed by hydrolysis of the thiolacetate withsodium hydroxide in a suitable solvent, typically in an alcohol such asethanol at ambient temperature. This thiol is then alkylated with theappropriate alkylating agent R¹⁸L where L is a leaving group such asbromide, iodide, tosylate, triflate or tosylate to give the desiredcompound of Formula 21

The desired Formula 21A compounds wherein n is 1 or 2, may be preparedfrom the corresponding sulfide of Formula 21 by treatment with anoxidizing agent such as hydrogen peroxide or m-chloroperbenzoic acid ina reaction inert solvent such as dichloromethane. The desired degree ofoxidation may be controlled by those skilled in the art and is usuallyachieved by appropriate choice of reaction temperature.

According to Scheme 4 the desired compounds of Formula I in which A, B,X, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as described above may beobtained by alkylation of a secondary amine of Formula 10 by a compoundof Formula 22 in the presence of a suitable base such as triethylamine,diisopropylethylamine, potassium carbonate, sodium hydride or potassiumtert-butoxide, preferably potassium tert-butoxide in a suitable reactioninert solvent such as THF, methylene chloride or dioxane, preferablyTHF, at a temperature between −40° C. and 40° C., preferably 0-30° C.

The compounds of Formula 22 may be prepared from the correspondingcompound of Formula 23 by conversion of the alcohol to a leaving group Lsuch as a mesylate, tosylate, triflate, chloride or bromide by standardprocedures known to those skilled in the art. For example a bromide maybe prepared by reacting compounds of Formula 17 using a suitable reagentsuch as phosphorus tribromide or a combination of carbon tetrabromideand triphenylphosphine in a reaction inert solvent such as methylenechloride, THF, or dioxan. The preferred reagent is a combination ofcarbon tetrabromide and triphenylphosphine, and the preferred solvent ismethylene chloride at a temperature between −78° C. and 100° C.,preferably −10° C. to 30° C.

The compounds of Formula 23 may be prepared from the correspondingcompounds of either Formula 24 or Formula 25 with an appropriatereducing agent well known to those skilled in the art, such as lithiumaluminum hydride, sodium borohydride or borane-THF complex as can befound in L. A. Paquette (Ed), Encyclopedia of Reagents for OrganicSynthesis, John Wiley and Sons, Chichester, England, 1995.

In another aspect of this invention the compounds of Formula I may beprepared from compounds of Formula 26 by a variety of methods well knownto those skilled in the arts. For example in the case where A is anoptionally substituted aromatic ring it is often possible to use theappropriate halogen derivative of A and displace the halogen with thesecondary amine of the Formula 13 compound generally in the presence ofa base. Frequently these reactions are facilitated by the use of apalladium catalyst as described in U.S. Pat. No. 5,576,460;International Publication No. WO 98/15515; International Publication No.WO00/02887; International Publication No. WO04/052939; EuropeanPublication No. EP3009560.8; and European Publication No. EP99933785.0;all of which are incorporated herein in their entireties for allpurposes. In another example when A is an optionally substituted2-pyridyl, 2- or 4-pyrimidinyl or 2-pyrazinyl group this reaction can beachieved without the use of a catalyst by use of the corresponding2-halopyridine, 2- or 4-halopyrimidine or 2-pyrazine respectively in asuitable reaction inert solvent such as dimethylformamide (DMF),N-methylpyrrolidinone or N,N,N′,N′-tetramethylurea using a suitable basesuch as triethylamine, diisopropylethylamine, potassium carbonate, orsodium carbonate. The preferred base is diisopropylethylamine in asuitable inert solvent such as THF, methylene chloride, DMF or dioxan.The preferred solvent is DMF at a temperature between −40° C. and 160°C., preferably 20° C.-140° C.

In another aspect of this invention the compounds of Formula I may beprepared from compounds of Formula 26 by a series of reactions, whichare well known to those skilled in the art, during which the A ring isconstructed de novo. Preferred examples of such processes include, butare not limited to, the reaction of the Formula 26 compounds with acyanating agent, such as cyanogen bromide or N-cyanoimidazole to producea cyanamide intermediate. This may be further reacted with an azidesource such as sodium azide, tri-n-butyltin azide or trimethylsilylazideto produce a tetrazole. Said tetrazole may be further reacted ifdesired, for example by alkylation. In another aspect, the saidcyanamide intermediate may be reacted with hydroxylamine followed by analkanoylating agent such as an acyl chloride to produce an oxadiazolecompound (Ried, W and Eichhorn, T. A., Archiv der Pharmazie 1998,321(9), 527). In yet another aspect, the said cyanamide intermediate maybe reacted with an acylhydrazide to produce a triazole ring-containingcompound (Ried, W and Eichhorn, T. A., Archiv der Pharmazie 1998,321(9), 527).

The compounds of Formula 26 may be prepared from the correspondingcompound of Formula 27 by reductive alkyation with a compound of Formula8 with a suitable reducing agent such as sodium borohydride, sodiumtriacetoxyborohydride, or sodium cyanoborohydride. The preferablereducing agent is sodium borohydride in a suitable solvent such asethanol, THF, methylene chloride, dioxan, or toluene. The preferredsolvent is ethanol at a temperature of −78° C. and 67° C. preferably0-50° C.

In another aspect of this invention the compounds of Formula 26 may beprepared from the corresponding compound of Formula 25 by reductivealkyation with an amine of Formula 11 with a suitable reducing agentsuch as sodium borohydride, sodium triacetoxyborohydride, or sodiumcyanoborohydride. The preferable reducing agent is sodium borohydride ina suitable solvent such as ethanol, THF, methylene chloride, dioxan, ortoluene. The preferred solvent is ethanol at a temperature of −78° C.and 67° C. preferably 0-50° C.

The compounds of Formula 27 may be prepared from the correspondingcompound of Formula 28 by reduction with a suitable reducing agent suchas lithium aluminum hydride as can be found in L. A. Paquette (Ed),Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons,Chichester, England, 1995.

In another aspect of this invention the compounds of Formula I may beprepared from compounds of Formula 29 and Formula 12 using a suitablebase such as triethylamine, diisopropylethylamine, potassium carbonate,sodium hydride or potassium tert-butoxide, preferably potassiumtert-butoxide in a suitable reaction inert solvent such as THF,methylene chloride or dioxane, preferably THF, at a temperature between−40° C. and 40° C., preferably 0-30° C.

Compounds of Formula 29 may be prepared from compounds of Formula 27 bya variety of methods well known to those skilled in the arts. Forexample in the case where A is an optionally substituted aromatic ringit is often possible to use the appropriate halogen derivative of A anddisplace the halogen with the primary amine of Formula 27 compoundgenerally in the presence of a base. Frequently these reactions arefacilitated by the use of a palladium catalyst as described in U.S. Pat.No. 5,576,460; International Publication No. WO 98/15515; InternationalPublication No. WO00/02887; International Publication No. WO04/052939;European Publication No. EP3009560.8; and European Publication No.EP99933785.0; all of which are incorporated herein in their entiretiesfor all purposes. In another example when A is an optionally substituted2-pyridyl, 2- or 4-pyrimidinyl or 2-pyrazinyl group this reaction can beachieved without the use of a catalyst by use of the corresponding2-halopyridine, 2- or 4-halopyrimidine or 2-pyrazine respectively in asuitable reaction inert solvent such as dimethylformamide (DMF),N-methylpyrrolidinone or N,N,N′,N′-tetramethylurea using a suitable basesuch as triethylamine, diisopropylethylamine, potassium carbonate, orsodium carbonate. The preferred base is diisopropylethylamine in asuitable inert solvent such as THF, methylene chloride, DMF or dioxan.The preferred solvent is DMF at a temperature between −40° C. and 160°C., preferably 20° C.-140° C.

According to Scheme 5 the compound of Formula 30 in which X, R¹, R², R³,R⁴, and R¹¹ are as described above and Hal is chloro, bromo or iodo canbe prepared from the compound of Formula 4 by reaction with theappropriate carboxylic acid in the presence of a suitable base such astriethylamine, diisopropylethylamine, potassium carbonate, cesiumcarbonate, sodium hydride or potassium tert-butoxide, preferably cesiumcarbonate in a suitable reaction inert solvent such as THF or DMF,preferably DMF, at a temperature between −40° C. and 40° C., preferably0-30° C.

The compound of Formula 31 may be obtained from a compound of Formula 30by treatment with a suitable organometallic reagent such asn-butyllithium, s-butyllithium or t-butyllithium, preferablys-butyllithium in a suitable reaction inert solvent such as THF at atemperature between −98° C. and 20° C., preferably −98° C. and 0° C.Depending on the nature of the substituents and the solvent in which itis dissolved this lactol may exist partially or completely in thering-opened, or hydroxyketone form.

The compound of Formula 32 may be prepared from the correspondingcompound of Formula 31 by treatment with a suitable reducing agent suchas sodium borohydride, sodium triacetoxyborohydride or lithium aluminumhydride in a suitable reaction inert solvent to give the desired alcoholof Formula 32. Preferred conditions utilize sodium borohydride inethanol between 0° C. and 40° C., preferably 20° C.

The compound of Formula 33, where P is an appropriate protecting groupsuch as trityl, allyl, tertbutyldimethylsilyl or triisopropylsilyl maybe prepared from the compound of Formula 32 by selective reaction at theless hindered alcohol group by procedures well known to those skilled inthe art such as those described in T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, New York,USA, 1991. Particularly preferred is the triisopropylsilyl derivativewhich is prepared by treatment of the alcohol with triisopropylsilylchloride in the presence of a suitable base such as imidazole in asuitable reaction inert solvent such as THF or DMF, preferably DMF, at atemperature between −40° C. and 40° C., preferably 0-30° C.

The compound of Formula 34 may be prepared from the correspondingalcohol of Formula 33 by an alkylation reaction well known to thoseskilled in the art for example as described in L. A. Paquette (Ed),Encyclopedia of Reagents for Organic Synthesis. John Wiley and Sons,Chichester, England, 1995. In a preferred aspect of this invention thealcohol may be treated with a base such as sodium hexamethyldisilazide,potassium hydride or sodium hydride, preferably sodium hydride, in areaction inert solvent such as THF and reacted with the appropriatealkylating agent R17L where L is a leaving group such as bromide,iodide, tosylate, triflate or tosylate to give the desired compound ofFormula 34.

The compound of Formula 23 wherein X, R¹, R², R³, R⁴ are as describedabove, Y is CHR¹¹ and B is OR¹⁷, herein designated Formula 35, may beprepared from the compound of Formula 34 by deprotection by procedureswell known to those skilled in the art such as those described in T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley and Sons, New York, USA, 1991. In the preferred case where P isthe triisopropylsilyl group the protecting group may be removed bytreatment with a fluoride source, preferably tetrabutylammoniumfluoride, in a suitable reaction inert solvent such as THF or DCM,preferably THF, at a temperature between −40° C. and 40° C., preferably0-30° C.

According to Scheme 6, the compound of Formula 36 wherein X, R¹, R², R³,and R⁴ are as described above and Hal is chloro, bromo or iodo,preferably bromo or iodo and P is an appropriate protecting group suchas trityl, allyl, tertbutyldimethylsilyl or triisopropylsilyl may beprepared from the compound of Formula 3 by procedures well known tothose skilled in the art such as those described in T. W. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons,New York, USA, 1991. Particularly preferred is the case where P istriisopropylsilyl which may be prepared by treatment of the alcohol withtriisopropylsilyl chloride in the presence of a suitable base such asimidazole in a suitable reaction inert solvent such as THF or DMF,preferably DMF, at a temperature between −40° C. and 40° C., preferably0-30° C.

The compound of Formula 37 wherein Y is CR¹¹R¹² may be prepared from thecompound of Formula 36 by treatment with a suitable organometallicreagent such as n-butyllithium, s-butyllithium, t-butyllithium orisopropylmagnesium chloride, preferably n-butyllithium orisopropylmagnesium chloride in a suitable reaction inert solvent such asTHF or diethyl ether at a temperature between −98° C. and 20° C.,preferably −78° C. to 0° C., followed after a suitable interval bytreatment with the carbonyl compound YO.

The compound of Formula 38, wherein B is OR¹⁷ or SR¹⁸ may be preparedfrom the alcohol of Formula 37 by the procedures described along withScheme 3.

In an alternative preparation of the compound of Formula 23, wherein X,Y, B, R¹, R², R³, R⁴ are as described above, the compound of Formula 34may be deprotected by procedures well known to those skilled in the artsuch as those described in T. W. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley and Sons, New York, USA, 1991.In the case where P is the triisopropylsilyl or tertbutyldimethylsilylgroup the protecting group may be removed by treatment with a fluoridesource, preferably tetrabutylammonium fluoride, in a suitable reactioninert solvent such as THF or DCM, preferably THF, at a temperaturebetween −40° C. and 40° C., preferably 0-30° C.

According to reaction Scheme 7, Hal is a halogen, X is C, and R¹, R²,R³, R⁴, R⁵, R⁶ and R⁷ are as described above. The desired compoundsdepicted as Formula 41 in Scheme 5, may be prepared from compounds ofFormulas 7 and 40 by acid hydrolysis, for example in the presence oftoluene sulfonic acid in a suitable solvent such as acetone, toluene,THF, or methylene chloride, preferably toluene, at a temperature between0° C. and reflux, preferably room temperature.

Compounds of Formula 13 may be prepared by hydrating the double bond ofFormula 41 by reaction with a reducing agent such as sodium borohydride,sodium triacetoxyborohydride, or sodium cyanoborohydride in a suitablesolvent such as ethanol. The reaction proceeds at a temperature between0° C. and 78° C., preferably between 20° C. and 50° C.

Compounds of Formula 42 may be prepared by reacting the amine of Formula13 in a suitable base such as sodium acetate and a suitable solvent suchas dichloromethane, and/or ethanol with a cyanating agent, such ascyanogen bromide or N-cyanoimidazole at ambient temperature. When thereaction is judged complete, it is purified into an oil.

Compounds of Formula 43 may be prepared by reacting the cyano-aminecompound of Formula 42 with an azide source such as sodium azide,tri-n-butyltin azide or trimethylsilylazide in a solvent such astoluene, THF, or methylene chloride, preferably toluene at a temperatureof 20° C. to 80° C.

A mixture of the methylated tetrazole-amine compounds having Formulas 44and 45 are produced by alkylating the compound of Formula 43 with analkylating agent such as dimethyl sulfate in a solvent such as 2-methylTHF, DMF and DMAc at a temperature of about 20° C. to 80° C.

Methyl 5-aminotetrazole may be produced by hydrogenating the mixture ofthe compounds of Formulas 44 and 45 using a hydrogenation catalyst suchas palladium on carbon or palladium hydroxide under a hydrogenatmosphere of 35 to 70 psi, preferably 40 psi in a reaction inertsolvent such as methanol, ethanol or acetic acid at a temperature of−78° to 70° C., preferably −78° C. to 40° C. Further methods forproducing this compound are published in PCT patent application Nos.WO2006/056854 and WO2006/03302, which are incorporated herein.

As an initial note, in the preparation of compounds, it is noted thatsome of the preparation methods useful for the preparation of thecompounds described herein may require protection of remotefunctionality (e.g., primary amine, secondary amine, carboxyl inintermediates). The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. The need for such protection is readily determined by oneskilled in the art. The use of such protection/deprotection methods isalso within the skill in the art. For a general description ofprotecting groups and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

For example, in the reaction schemes, certain compounds contain primaryamines or carboxylic acid functionalities which may interfere withreactions at other sites of the molecule if left unprotected.Accordingly, such functionalities may be protected by an appropriateprotecting group which may be removed in a subsequent step. Suitableprotecting groups for amine and carboxylic acid protection include thoseprotecting groups commonly used in peptide synthesis (such asN-t-butoxycarbonyl, benzyloxycarbonyl, and9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzylesters for carboxylic acids) which are generally not chemically reactiveunder the reaction conditions described and can typically be removedwithout chemically altering other functionality in the compound.

Prodrugs of the compounds of the present invention may be preparedaccording to methods known to those skilled in the art. Exemplaryprocesses are described below.

Prodrugs of this invention where a carboxyl group in a carboxylic acidof the compounds is replaced by an ester may be prepared by combiningthe carboxylic acid with the appropriate alkyl halide in the presence ofa base such as potassium carbonate in an inert solvent such asdimethylformamide at a temperature of about 0 to 100° C. for about 1 toabout 24 hours. Alternatively the acid is combined with an appropriatealcohol as solvent in the presence of a catalytic amount of acid such asconcentrated sulfuric acid at a temperature of about 20 to 100° C.,preferably at a reflux, for about 1 hour to about 24 hours. Anothermethod is the reaction of the acid with a stoichiometric amount of thealcohol in the presence of a catalytic amount of acid in an inertsolvent such as toluene or tetrahydrofuran, with concomitant removal ofthe water being produced by physical (e.g., Dean-Stark trap) or chemical(e.g., molecular sieves) means.

Prodrugs of this invention where an alcohol function has beenderivatized as an ether may be prepared by combining the alcohol withthe appropriate alkyl bromide or iodide in the presence of a base suchas potassium carbonate in an inert solvent such as dimethylformamide ata temperature of about 0 to 100° C. for about 1 to about 24 hours.Alkanoylaminomethyl ethers may be obtained by reaction of the alcoholwith a bis-(alkanoylamino)methane in the presence of a catalytic amountof acid in an inert solvent such as tetrahydrofuran, according to amethod described in U.S. Pat. No. 4,997,984. Alternatively, thesecompounds may be prepared by the methods described by Hoffman et al. inJ. Org. Chem. 1994, 59, 3530.

Glycosides are prepared by reaction of the alcohol and a carbohydrate inan inert solvent such as toluene in the presence of acid. Typically thewater formed in the reaction is removed as it is being formed asdescribed above. An alternate procedure is the reaction of the alcoholwith a suitably protected glycosyl halide in the presence of basefollowed by deprotection.

N-(1-hydroxyalkyl) amides, N-(1-hydroxy-1-(alkoxycarbonyl)methyl) amidesmay be prepared by the reaction of the parent amide with the appropriatealdehyde under neutral or basic conditions (e.g., sodium ethoxide inethanol) at temperatures between 25 and 70° C. N-alkoxymethyl orN-1-(alkoxy)alkyl derivatives can be obtained by reaction of theN-unsubstituted compound with the necessary alkyl halide in the presenceof a base in an inert solvent.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents (e.g., LDL-cholesterol lowering agents,triglyceride lowering agents) for the treatment of thedisease/conditions described herein. For example, they may be used incombination with a HMG-CoA reductase inhibitor, a cholesterol synthesisinhibitor, a cholesterol absorption inhibitor, another CETP inhibitor, aMTP/Apo B secretion inhibitor, a PPAR modulator and other cholesterollowering agents such as a fibrate, niacin, an ion-exchange resin, anantioxidant, an ACAT inhibitor, and a bile acid sequestrant. Otherpharmaceutical agents would also include the following: a bile acidreuptake inhibitor, an ileal bile acid transporter inhibitor, an ACCinhibitor, an antihypertensive (such as NORVASC®), a selective estrogenreceptor modulator, a selective androgen receptor modulator, anantibiotic, an antidiabetic (such as metformin, a PPARγ activator, asulfonylurea, insulin, an aldose reductase inhibitor (ARI) and asorbitol dehydrogenase inhibitor (SDI)), and aspirin (acetylsalicylicacid or a nitric oxide releasing asprin). As used herein, “niacin”includes all available forms such as immediate release, slow release,extended release and low-flushing niacin. Niacin may also be combinedwith other therapeutic agents such as prostaglandins and/or statins,i.e. lovastatin or simvastatin, which are an HMG-CoA reductase inhibitorand described further below. This combination therapy is known asADVICOR® (Kos Pharmaceuticals Inc.) In combination therapy treatment,both the compounds of this invention and the other drug therapies areadministered to mammals (e.g., humans, male or female) by conventionalmethods.

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) tomevalonate is an early and rate-limiting step in the cholesterolbiosynthetic pathway. This step is catalyzed by the enzyme HMG-CoAreductase. Statins inhibit HMG-CoA reductase from catalyzing thisconversion. Exemplary statins include lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin,pitavastatin,(3R,5R)-7-(4-(benzylcarbamoyl)-2-(4-fluorophenyl)-5-isopropyl-1H-imidazol-1-yl)-3,5-dihydroxyheptanoicacid;(3R,5R)-7-(4((4-methylbenzyl)carbamoyl)-2-(4-fluorophenyl)-5-isopropyl-1H-pyrazol-1-yl)-3,5-dihydroxyheptanoicacid; and(3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoicacid, and pharmaceutically acceptable salts thereof.

Atorvastatin calcium (i.e., atorvastatin hemicalcium), disclosed in U.S.Pat. No. 5,273,995, which is incorporated herein by reference, iscurrently sold as Lipitor® and has the formula

Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA.As such, atorvastatin calcium is a potent lipid lowering compound. Thefree carboxylic acid form of atorvastatin exists predominantly as thelactone of the formula

and is disclosed in U.S. Pat. No. 4,681,893, which is incorporatedherein by reference.

Statins include such compounds as rosuvastatin disclosed in U.S.RE37,314 E, pitivastatin disclosed in EP 304063 B1 and U.S. Pat. No.5,011,930, simvastatin, disclosed in U.S. Pat. No. 4,444,784, which isincorporated herein by reference; pravastatin, disclosed in U.S. Pat.No. 4,346,227 which is incorporated herein by reference; cerivastatin,disclosed in U.S. Pat. No. 5,502,199, which is incorporated herein byreference; mevastatin, disclosed in U.S. Pat. No. 3,983,140, which isincorporated herein by reference; velostatin, disclosed in U.S. Pat. No.4,448,784 and U.S. Pat. No. 4,450,171, both of which are incorporatedherein by reference; fluvastatin, disclosed in U.S. Pat. No. 4,739,073,which is incorporated herein by reference; compactin, disclosed in U.S.Pat. No. 4,804,770, which is incorporated herein by reference;lovastatin, disclosed in U.S. Pat. No. 4,231,938, which is incorporatedherein by reference; dalvastatin, disclosed in European PatentApplication Publication No 738510 A2; fluindostatin, disclosed inEuropean Patent Application Publication No. 363934 A1; atorvastatin,disclosed in U.S. Pat. No. 4,681,893, which is incorporated herein byreference; atorvastatin calcium (which is the hemicalcium salt ofatorvastatin), disclosed in U.S. Pat. No. 5,273,995, which isincorporated herein by reference; and dihydrocompactin, disclosed inU.S. Pat. No. 4,450,171, which is incorporated herein by reference.

Further HMG CoA reductase inhibitors are disclosed in InternationalPublication Nos. WO 2005/105079; and PCT/IB2005/003461 filed Nov. 14,2005 (the disclosures of which are hereby incorporated by reference)including (3R,5R)-7-(4-(benzylcarbamoyl)2-(4-fluorophenyl)-5-isopropyl-1H-imidazol-1-yl)-3,5-dihydroxyheptanoicacid;(3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid; and(3R,5R)-7-(4-((4-methylbenzyl)carbamoyl)-2-(4-fluorophenyl)-5-isopropyl-1H-pyrazol-1-yl)-3,5-dihydroxyheptanoicacid and pharmaceutically acceptable salts of said compounds.

Any PPAR modulator may be used in the combination aspect of thisinvention. The term PPAR modulator refers to compounds which modulateperoxisome proliferator activator receptor (PPAR) activity in mammals,particularly humans. Such modulation is readily determined by thoseskilled in the art according to standard assays known in the literature.It is believed that such compounds, by modulating the PPAR receptor,regulate transcription of key genes involved in lipid and glucosemetabolism such as those in fatty acid oxidation and also those involvedin high density lipoprotein (HDL) assembly (for example, apolipoproteinAl gene transcription), accordingly reducing whole body fat andincreasing HDL cholesterol. By virtue of their activity, these compoundsalso reduce plasma levels of triglycerides, VLDL cholesterol, LDLcholesterol and their associated components such as apolipoprotein B inmammals, particularly humans, as well as increasing HDL cholesterol andapolipoprotein Al. Hence, these compounds are useful for the treatmentand correction of the various dyslipidemias observed to be associatedwith the development and incidence of atherosclerosis and cardiovasculardisease, including hypoalphalipoproteinemia and hypertriglyceridemia. Avariety of these compounds are described and referenced below, however,others will be known to those skilled in the art. InternationalPublication Nos. WO 2004/048334; WO 2005/092845; and WO 2006/003495 (thedisclosures of which are hereby incorporated by reference) disclosecertain compounds which are PPARα activators including3-[3-(1-Carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid3-trifluoromethyl-benzyl ester;3-[3-(1-Carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid4-trifluoromethyl-benzyl ester;5-[4-(4-Ethyl-benzylsulfanyl)-phenylsulfamoyl]-2-methyl-benzoic acid;and5-{2-[4-(3,4-Difluoro-phenoxy)-phenyl]-ethylsulfamoyl}-2-methyl-benzoicacid; and pharmaceutically acceptable salts of said compounds.

Any other PPAR modulator may be used in the combination aspect of thisinvention. In particular, modulators of PPARβ and/or PPARγ may be usefulin combination with compounds of the present invention. Exemplary PPARinhibitors are described in International Publication No. WO 2003/084916as{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfany]-phenoxy}-aceticacid and{5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid; and pharmaceutically acceptable salts of said compounds.

Any MTP/Apo B (microsomal triglyceride transfer protein and orapolipoprotein B) secretion inhibitor may be used in the combinationaspect of this invention. The term MTP/Apo B secretion inhibitor refersto compounds which inhibit the secretion of triglycerides, cholesterylester, and phospholipids. Such inhibition is readily determined by thoseskilled in the art according to standard assays (e.g., Wetterau, J. R.1992; Science 258:999). A variety of these compounds are described andreferenced below however other MTP/Apo B secretion inhibitors will beknown to those skilled in the art, including implitapide (Bayer) andadditional compounds such as those disclosed in WO 96/40640 and WO98/23593, (two exemplary publications).

For example, the following MTP/Apo B secretion inhibitors areparticularly useful:

-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    [2-(1H-[1,2,4,]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    [2-(2-acetylamino-ethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;-   (2-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)carbamic    acid methyl ester;-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    [2-(1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    [2-(2,2-diphenyl-ethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    [2-(2-ethoxy-ethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;-   (S)—N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide;-   (S)-2-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic    acid (pentylcarbamoyl-phenyl-methyl)-amide;-   1H-indole-2-carboxamide,    1-methyl-N-[(1S)-2-[methyl(phenylmethyl)amino]-2-oxo-1-phenylethyl]-5-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino];    and-   N-[(1S)-2-(benzylmethylamino)-2-oxo-1-phenylethyl]-1-methyl-5-[[[4′-(trifluoromethyl)biphenyl-2-yl]carbonyl]amino]-1H-indole-2-carboxamide.

Any HMG-CoA synthase inhibitor may be used in the combination aspect ofthis invention. The term HMG-CoA synthase inhibitor refers to compoundswhich inhibit the biosynthesis of hydroxymethylglutaryl-coenzyme A fromacetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzymeHMG-CoA synthase. Such inhibition is readily determined by those skilledin the art according to standard assays (Meth Enzymol. 1975; 35:155-160:Meth. Enzymol. 1985; 110:19-26 and references cited therein). A varietyof these compounds are described and referenced below, however otherHMG-CoA synthase inhibitors will be known to those skilled in the art.U.S. Pat. No. 5,120,729 (the disclosure of which is hereby incorporatedby reference) discloses certain beta-lactam derivatives. U.S. Pat. No.5,064,856 (the disclosure of which is hereby incorporated by reference)discloses certain spiro-lactone derivatives prepared by culturing amicroorganism (MF5253). U.S. Pat. No. 4,847,271 (the disclosure of whichis hereby incorporated by reference) discloses certain oxetane compoundssuch as11-(3-hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undeca-dienoicacid derivatives.

Any compound that decreases HMG-CoA reductase gene expression may beused in the combination aspect of this invention. These agents may beHMG-CoA reductase transcription inhibitors that block the transcriptionof DNA or translation inhibitors that prevent or decrease translation ofmRNA coding for HMG-CoA reductase into protein. Such compounds mayeither affect transcription or translation directly, or may bebiotransformed to compounds that have the aforementioned activities byone or more enzymes in the cholesterol biosynthetic cascade or may leadto the accumulation of an isoprene metabolite that has theaforementioned activities. Such compounds may cause this effect bydecreasing levels of SREBP (sterol receptor binding protein) byinhibiting the activity of site-1 protease (S1P) or agonizing theoxzgenal receptor or SCAP. Such regulation is readily determined bythose skilled in the art according to standard assays (Meth. Enzymol.1985; 110:9-19). Several compounds are described and referenced below,however other inhibitors of HMG-CoA reductase gene expression will beknown to those skilled in the art. U.S. Pat. No. 5,041,432 (thedisclosure of which is incorporated by reference) discloses certain15-substituted lanosterol derivatives. Other oxygenated sterols thatsuppress synthesis of HMG-CoA reductase are discussed by E. I. Mercer(Prog. Lip. Res. 1993; 32:357-416).

Any additional compound having activity as a CETP inhibitor can serve asthe second compound in the combination therapy aspect of the presentinvention. The term CETP inhibitor refers to compounds that inhibit thecholesteryl ester transfer protein (CETP) mediated transport of variouscholesteryl esters and triglycerides from HDL to LDL and VLDL. Such CETPinhibition activity is readily determined by those skilled in the artaccording to standard assays (e.g., U.S. Pat. No. 6,140,343). A varietyof CETP inhibitors will be known to those skilled in the art, forexample, those disclosed in commonly assigned U.S. Pat. No. 6,140,343and commonly assigned U.S. Pat. No. 6,197,786. CETP inhibitors disclosedin these patents include compounds, such as [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, which is also known as torcetrapib. CETP inhibitorsare also described in U.S. Pat. No. 6,723,752, which includes a numberof CETP inhibitors including(2R)-3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-methyl]-amino}-1,1,1-trifluoro-2-propanol.Moreover, CETP inhibitors included herein are also described in U.S.patent application Ser. No. 10/807,838 filed Mar. 23, 2004. U.S. Pat.No. 5,512,548 discloses certain polypeptide derivatives having activityas CETP inhibitors, while certain CETP-inhibitory rosenonolactonederivatives and phosphate-containing analogs of cholesteryl ester aredisclosed in J. Antibiot., 49(8): 815-816 (1996), and Bioorg. Med. Chem.Lett.; 6:1951-1954 (1996), respectively.

Exemplary CETP inhibitors include[2R,4S]-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;cis-(2R,4S)-2-(4-{4-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl}-cyclohexyl)-acetamide;(2R)-3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methyl]-amino}-1,1,1-trifluoro-2-propanol;and (2R, 4R,4aS)-4-[Amino-(3,5-bis-trifluoromethyl-phenyl)methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester or a pharmaceutically acceptable salt of saidcompounds.

Any squalene synthetase inhibitor may be used in the combination aspectof this invention. The term squalene synthetase inhibitor refers tocompounds which inhibit the condensation of 2 molecules offarnesylpyrophosphate to form squalene, catalyzed by the enzyme squalenesynthetase. Such inhibition is readily determined by those skilled inthe art according to standard assays (Meth. Enzymol. 1969; 15: 393-454and Meth. Enzymol. 1985; 110:359-373 and references contained therein).A variety of these compounds are described in and referenced belowhowever other squalene synthetase inhibitors will be known to thoseskilled in the art. U.S. Pat. No. 5,026,554 (the disclosure of which isincorporated by reference) discloses fermentation products of themicroorganism MF5465 (ATCC 74011) including zaragozic acid. A summary ofother patented squalene synthetase inhibitors has been compiled (Curr.Op. Ther. Patents (1993) 861-4).

Any squalene epoxidase inhibitor may be used in the combination aspectof this invention. The term squalene epoxidase inhibitor refers tocompounds which inhibit the bioconversion of squalene and molecularoxygen into squalene-2,3-epoxide, catalyzed by the enzyme squaleneepoxidase. Such inhibition is readily determined by those skilled in theart according to standard assays (Biochim. Biophys. Acta 1984;794:466-471). A variety of these compounds are described and referencedbelow, however other squalene epoxidase inhibitors will be known tothose skilled in the art. U.S. Pat. Nos. 5,011,859 and 5,064,864 (thedisclosures of which are incorporated by reference) disclose certainfluoro analogs of squalene. EP publication 395,768 A (the disclosure ofwhich is incorporated by reference) discloses certain substitutedallylamine derivatives. PCT publication WO 9312069 A (the disclosure ofwhich is hereby incorporated by reference) discloses certain aminoalcohol derivatives. U.S. Pat. No. 5,051,534 (the disclosure of which ishereby incorporated by reference) discloses certaincyclopropyloxy-squalene derivatives.

Any squalene cyclase inhibitor may be used as the second component inthe combination aspect of this invention. The term squalene cyclaseinhibitor refers to compounds which inhibit the bioconversion ofsqualene-2,3-epoxide to lanosterol, catalyzed by the enzyme squalenecyclase. Such inhibition is readily determined by those skilled in theart according to standard assays (FEBS Lett. 1989; 244:347-350.). Inaddition, the compounds described and referenced below are squalenecyclase inhibitors, however other squalene cyclase inhibitors will alsobe known to those skilled in the art. PCT publication WO9410150 (thedisclosure of which is hereby incorporated by reference) disclosescertain1,2,3,5,6,7,8,8a-octahydro-5,5,8(beta)-trimethyl-6-isoquinolineaminederivatives, such asN-trifluoroacetyl-1,2,3,5,6,7,8,8a-octahydro-2-allyl-5,5,8(beta)-trimethyl-6(beta)-isoquinolineamine.French patent publication 2697250 (the disclosure of which is herebyincorporated by reference) discloses certain beta,beta-dimethyl-4-piperidine ethanol derivatives such as1-(1,5,9-trimethyldecyl)-beta, beta-dimethyl-4-piperidineethanol

Any combined squalene epoxidase/squalene cyclase inhibitor may be usedas the second component in the combination aspect of this invention. Theterm combined squalene epoxidase/squalene cyclase inhibitor refers tocompounds that inhibit the bioconversion of squalene to lanosterol via asqualene-2,3-epoxide intermediate. In some assays it is not possible todistinguish between squalene epoxidase inhibitors and squalene cyclaseinhibitors, however, these assays are recognized by those skilled in theart. Thus, inhibition by combined squalene epoxidase/squalene cyclaseinhibitors is readily determined by those skilled in art according tothe aforementioned standard assays for squalene cyclase or squaleneepoxidase inhibitors. A variety of these compounds are described andreferenced below, however other squalene epoxidase/squalene cyclaseinhibitors will be known to those skilled in the art. U.S. Pat. Nos.5,084,461 and 5,278,171 (the disclosures of which are incorporated byreference) disclose certain azadecalin derivatives. EP publication468,434 (the disclosure of which is incorporated by reference) disclosescertain piperidyl ether and thio-ether derivatives such as2-(1-piperidyl)pentyl isopentyl sulfoxide and 2-(1-piperidyl)ethyl ethylsulfide. PCT publication WO 9401404 (the disclosure of which is herebyincorporated by reference) discloses certain acyl-piperidines such as1-(1-oxopentyl-5-phenylthio)-4-(2-hydroxy-1-methyl)-ethyl)piperidine.U.S. Pat. No. 5,102,915 (the disclosure of which is hereby incorporatedby reference) discloses certain cyclopropyloxy-squalene derivatives.

The compounds of the present invention may also be administered incombination with naturally occurring compounds that act to lower plasmacholesterol levels. These naturally occurring compounds are commonlycalled nutraceuticals and include, for example, garlic extract andniacin. A slow-release form of niacin is available and is known asNiaspan. Niacin may also be combined with other therapeutic agents suchas lovastatin, or another is an HMG-CoA reductase inhibitor. Thiscombination therapy with lovastatin is known as ADVICOR™ (KosPharmaceuticals Inc.).

Any cholesterol absorption inhibitor can be used as an additional in thecombination aspect of the present invention. The term cholesterolabsorption inhibition refers to the ability of a compound to preventcholesterol contained within the lumen of the intestine from enteringinto the intestinal cells and/or passing from within the intestinalcells into the lymph system and/or into the blood stream. Suchcholesterol absorption inhibition activity is readily determined bythose skilled in the art according to standard assays (e.g., J. LipidRes. (1993) 34: 377-395). Cholesterol absorption inhibitors are known tothose skilled in the art and are described, for example, in PCT WO94/00480. An example of a recently approved cholesterol absorptioninhibitor is ZETIA™ (ezetimibe) (Schering-Plough/Merck).

Any ACAT inhibitor may be used in the combination therapy aspect of thepresent invention. The term ACAT inhibitor refers to compounds thatinhibit the intracellular esterification of dietary cholesterol by theenzyme acyl CoA: cholesterol acyltransferase. Such inhibition may bedetermined readily by one of skill in the art according to standardassays, such as the method of Heider et al. described in Journal ofLipid Research., 24:1127 (1983). A variety of these compounds are knownto those skilled in the art, for example, U.S. Pat. No. 5,510,379discloses certain carboxysulfonates, while WO 96/26948 and WO 96/10559both disclose urea derivatives having ACAT inhibitory activity. Examplesof ACAT inhibitors include compounds such as Avasimibe (Pfizer), CS-505(Sankyo) and Eflucimibe (Eli Lilly and Pierre Fabre).

A lipase inhibitor may be used in the combination therapy aspect of thepresent invention. A lipase inhibitor is a compound that inhibits themetabolic cleavage of dietary triglycerides or plasma phospholipids intofree fatty acids and the corresponding glycerides (e.g. EL, HL, etc.).Under normal physiological conditions, lipolysis occurs via a two-stepprocess that involves acylation of an activated serine moiety of thelipase enzyme. This leads to the production of a fatty acid-lipasehemiacetal intermediate, which is then cleaved to release a diglyceride.Following further deacylation, the lipase-fatty acid intermediate iscleaved, resulting in free lipase, a glyceride and fatty acid. In theintestine, the resultant free fatty acids and monoglycerides areincorporated into bile acid-phospholipid micelles, which aresubsequently absorbed at the level of the brush border of the smallintestine. The micelles eventually enter the peripheral circulation aschylomicrons. Such lipase inhibition activity is readily determined bythose skilled in the art according to standard assays (e.g., MethodsEnzymol. 286: 190-231).

Pancreatic lipase mediates the metabolic cleavage of fatty acids fromtriglycerides at the 1- and 3-carbon positions. The primary site of themetabolism of ingested fats is in the duodenum and proximal jejunum bypancreatic lipase, which is usually secreted in vast excess of theamounts necessary for the breakdown of fats in the upper smallintestine. Because pancreatic lipase is the primary enzyme required forthe absorption of dietary triglycerides, inhibitors have utility in thetreatment of obesity and the other related conditions. Such pancreaticlipase inhibition activity is readily determined by those skilled in theart according to standard assays (e.g., Methods Enzymol. 286: 190-231).

Gastric lipase is an immunologically distinct lipase that is responsiblefor approximately 10 to 40% of the digestion of dietary fats. Gastriclipase is secreted in response to mechanical stimulation, ingestion offood, the presence of a fatty meal or by sympathetic agents. Gastriclipolysis of ingested fats is of physiological importance in theprovision of fatty acids needed to trigger pancreatic lipase activity inthe intestine and is also of importance for fat absorption in a varietyof physiological and pathological conditions associated with pancreaticinsufficiency. See, for example, C. K. Abrams, et al., Gastroenterology,92,125 (1987). Such gastric lipase inhibition activity is readilydetermined by those skilled in the art according to standard assays(e.g., Methods Enzymol. 286: 190-231).

A variety of gastric and/or pancreatic lipase inhibitors are known toone of ordinary skill in the art. Preferred lipase inhibitors are thoseinhibitors that are selected from the group consisting of lipstatin,tetrahydrolipstatin (orlistat), valilactone, esterastin, ebelactone A,and ebelactone B. The compound tetrahydrolipstatin is especiallypreferred. The lipase inhibitor,N-3-trifluoromethylphenyl-N′-3-chloro-4′-trifluoromethylphenylurea, andthe various urea derivatives related thereto, are disclosed in U.S. Pat.No. 4,405,644. The lipase inhibitor, esteracin, is disclosed in U.S.Pat. Nos. 4,189,438 and 4,242,453. The lipase inhibitor,cyclo-O,O′-[(1,6-hexanediyl)-bis-(iminocarbonyl)]dioxime, and thevarious bis(iminocarbonyl)dioximes related thereto may be prepared asdescribed in Petersen et al., Liebig's Annalen, 562, 205-229 (1949).

A variety of pancreatic lipase inhibitors are described herein below.The pancreatic lipase inhibitors lipstatin, (2S, 3S, 5S, 7Z,10Z)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-7,10-hexadecanoicacid lactone, and tetrahydrolipstatin (orlistat), (2S, 3S,5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoic1,3 acid lactone, and the variously substituted N-formylleucinederivatives and stereoisomers thereof, are disclosed in U.S. Pat. No.4,598,089. For example, tetrahydrolipstatin is prepared as described in,e.g., U.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. Thepancreatic lipase inhibitor, FL-386,1-[4-(2-methylpropyl)cyclohexyl]-2-[(phenylsulfonyl)oxy]-ethanone, andthe variously substituted sulfonate derivatives related thereto, aredisclosed in U.S. Pat. No. 4,452,813. The pancreatic lipase inhibitor,WAY-121898, 4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and thevarious carbamate esters and pharmaceutically acceptable salts relatedthereto, are disclosed in U.S. Pat. Nos. 5,512,565; 5,391,571 and5,602,151. The pancreatic lipase inhibitor, valilactone, and a processfor the preparation thereof by the microbial cultivation ofActinomycetes strain MG147-CF2, are disclosed in Kitahara, et al., J.Antibiotics, 40 (11), 1647-1650 (1987). The pancreatic lipaseinhibitors, ebelactone A and ebelactone B, and a process for thepreparation thereof by the microbial cultivation of Actinomycetes strainMG7-G1, are disclosed in Umezawa, et al., J. Antibiotics, 33, 1594-1596(1980). The use of ebelactones A and B in the suppression ofmonoglyceride formation is disclosed in Japanese Kokai 108-143457,published Jun. 4, 1996.

Other compounds that are marketed for hyperlipidemia, includinghypercholesterolemia and which are intended to help prevent or treatatherosclerosis include bile acid sequestrants, such as Welchol®Colestid®, LoCholest® and Questran®; and fibric acid derivatives, suchas Atromid®, Lopid® and Tricor®.

Diabetes can be treated by administering to a patient having diabetes(especially Type II), insulin resistance, impaired glucose tolerance,metabolic syndrome, or the like, or any of the diabetic complicationssuch as neuropathy, nephropathy, retinopathy or cataracts, atherapeutically effective amount of a compound of the present inventionin combination with other agents (e.g., insulin) that can be used totreat diabetes. This includes the classes of anti-diabetic agents (andspecific agents) described herein.

Any glycogen phosphorylase inhibitor can be used as the second agent incombination with a compound of the present invention. The term glycogenphosphorylase inhibitor refers to compounds that inhibit thebioconversion of glycogen to glucose-1-phosphate which is catalyzed bythe enzyme glycogen phosphorylase. Such glycogen phosphorylaseinhibition activity is readily determined by those skilled in the artaccording to standard assays (e.g., J. Med. Chem. 41 (1998) 2934-2938).A variety of glycogen phosphorylase inhibitors are known to thoseskilled in the art including those described in WO 96/39384 and WO96/39385.

Any aldose reductase inhibitor can be used in combination with acompound of the present invention. The term aldose reductase inhibitorrefers to compounds that inhibit the bioconversion of glucose tosorbitol, which is catalyzed by the enzyme aldose reductase. Aldosereductase inhibition is readily determined by those skilled in the artaccording to standard assays (e.g., J. Malone, Diabetes, 29:861-864(1980). “Red Cell Sorbitol, an Indicator of Diabetic Control”). Avariety of aldose reductase inhibitors are known to those skilled in theart, such as those described in U.S. Pat. No. 6,579,879, which includes6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one.

Any sorbitol dehydrogenase inhibitor can be used in combination with acompound of the present invention. The term sorbitol dehydrogenaseinhibitor refers to compounds that inhibit the bioconversion of sorbitolto fructose which is catalyzed by the enzyme sorbitol dehydrogenase.Such sorbitol dehydrogenase inhibitor activity is readily determined bythose skilled in the art according to standard assays (e.g., Analyt.Biochem (2000) 280: 329-331). A variety of sorbitol dehydrogenaseinhibitors are known, for example, U.S. Pat. Nos. 5,728,704 and5,866,578 disclose compounds and a method for treating or preventingdiabetic complications by inhibiting the enzyme sorbitol dehydrogenase.

Any glucosidase inhibitor can be used in combination with a compound ofthe present invention. A glucosidase inhibitor inhibits the enzymatichydrolysis of complex carbohydrates by glycoside hydrolases, for exampleamylase or maltase, into bioavailable simple sugars, for example,glucose. The rapid metabolic action of glucosidases, particularlyfollowing the intake of high levels of carbohydrates, results in a stateof alimentary hyperglycemia which, in adipose or diabetic subjects,leads to enhanced secretion of insulin, increased fat synthesis and areduction in fat degradation. Following such hyperglycemias,hypoglycemia frequently occurs, due to the augmented levels of insulinpresent. Additionally, it is known chyme remaining in the stomachpromotes the production of gastric juice, which initiates or favors thedevelopment of gastritis or duodenal ulcers. Accordingly, glucosidaseinhibitors are known to have utility in accelerating the passage ofcarbohydrates through the stomach and inhibiting the absorption ofglucose from the intestine. Furthermore, the conversion of carbohydratesinto lipids of the fatty tissue and the subsequent incorporation ofalimentary fat into fatty tissue deposits is accordingly reduced ordelayed, with the concomitant benefit of reducing or preventing thedeleterious abnormalities resulting therefrom. Such glucosidaseinhibition activity is readily determined by those skilled in the artaccording to standard assays (e.g., Biochemistry (1969) 8: 4214).

A generally preferred glucosidase inhibitor includes an amylaseinhibitor. An amylase inhibitor is a glucosidase inhibitor that inhibitsthe enzymatic degradation of starch or glycogen into maltose. Suchamylase inhibition activity is readily determined by those skilled inthe art according to standard assays (e.g., Methods Enzymol. (1955) 1:149). The inhibition of such enzymatic degradation is beneficial inreducing amounts of bioavailable sugars, including glucose and maltose,and the concomitant deleterious conditions resulting therefrom.

A variety of glucosidase inhibitors are known to one of ordinary skillin the art and examples are provided below. Preferred glucosidaseinhibitors are those inhibitors that are selected from the groupconsisting of acarbose, adiposine, voglibose, miglitol, emiglitate,camiglibose, tendamistate, trestatin, pradimicin-Q and salbostatin. Theglucosidase inhibitor, acarbose, and the various amino sugar derivativesrelated thereto are disclosed in U.S. Pat. Nos. 4,062,950 and 4,174,439respectively. The glucosidase inhibitor, adiposine, is disclosed in U.S.Pat. No. 4,254,256. The glucosidase inhibitor, voglibose,3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epi-inositol,and the various N-substituted pseudo-aminosugars related thereto, aredisclosed in U.S. Pat. No. 4,701,559. The glucosidase inhibitor,miglitol,(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol,and the various 3,4,5-trihydroxypiperidines related thereto, aredisclosed in U.S. Pat. No. 4,639,436. The glucosidase inhibitor,emiglitate, ethylp-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]ethoxy]-benzoate,the various derivatives related thereto and pharmaceutically acceptableacid addition salts thereof, are disclosed in U.S. Pat. No. 5,192,772.The glucosidase inhibitor, MDL-25637,2,6-dideoxy-7-O-β-D-glucopyrano-syl-2,6-imino-D-glycero-L-gluco-heptitol,the various homodisaccharides related thereto and the pharmaceuticallyacceptable acid addition salts thereof, are disclosed in U.S. Pat. No.4,634,765. The glucosidase inhibitor, camiglibose, methyl6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]-α-D-glucopyranosidesesquihydrate, the deoxy-nojirimycin derivatives related thereto, thevarious pharmaceutically acceptable salts thereof and synthetic methodsfor the preparation thereof, are disclosed in U.S. Pat. Nos. 5,157,116and 5,504,078. The glycosidase inhibitor, salbostatin and the variouspseudosaccharides related thereto, are disclosed in U.S. Pat. No.5,091,524.

A variety of amylase inhibitors are known to one of ordinary skill inthe art. The amylase inhibitor, tendamistat and the various cyclicpeptides related thereto, are disclosed in U.S. Pat. No. 4,451,455. Theamylase inhibitor AI-3688 and the various cyclic polypeptides relatedthereto are disclosed in U.S. Pat. No. 4,623,714. The amylase inhibitor,trestatin, consisting of a mixture of trestatin A, trestatin B andtrestatin C and the various trehalose-containing aminosugars relatedthereto are disclosed in U.S. Pat. No. 4,273,765.

Additional anti-diabetic compounds, which can be used as the secondagent in combination with a compound of the present invention, include,for example, the following: biguanides (e.g., metformin), insulinsecretagogues (e.g., sulfonylureas and glinides), glitazones,non-glitazone PPARγ agonists, PPARβ agonists, inhibitors of DPP-IV,inhibitors of PDE5, inhibitors of GSK-3, glucagon antagonists,inhibitors of f-1,6-BPase(Metabasis/Sankyo), GLP-1/analogs (AC 2993,also known as exendin-4), insulin and insulin mimetics (Merck naturalproducts). Other examples would include PKC-β inhibitors and AGEbreakers. The compounds of the present invention can be used incombination with anti-obesity agents. Any anti-obesity agent can be usedas the second agent in such combinations and examples are providedherein. Such anti-obesity activity is readily determined by thoseskilled in the art according to standard assays known in the art.

Suitable anti-obesity agents include phenylpropanolamine, ephedrine,pseudoephedrine, phentermine, β₃ adrenergic receptor agonists,apolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A)agonists, monoamine reuptake inhibitors (e.g., sibutramine),sympathomimetic agents, serotoninergic agents, cannabinoid receptor(CB-1) antagonists (e.g., rimonabant described in U.S. Pat. No.5,624,941 (SR-141,716A), purine compounds, such as those described in USPatent Publication No. 2004/0092520; pyrazolo[1,5-a][1,3,5]triazinecompounds, such as those described in U.S. Non-Provisional patentapplication Ser. No. 10/763,105 filed on Jan. 21, 2004; and bicyclicpyrazolyl and imidazolyl compounds, such as those described in U.S.Provisional Application No. 60/518,280 filed on Nov. 7, 2003), dopamineagonists (e.g., bromocriptine), melanocyte-stimulating hormone receptoranalogs, 5HT2c agonists, melanin concentrating hormone antagonists,leptin (the OB protein), leptin analogs, leptin receptor agonists,galanin antagonists, lipase inhibitors (e.g., tetrahydrolipstatin, i.e.orlistat), bombesin agonists, anorectic agents (e.g., a bombesinagonist), Neuropeptide-Y antagonists, thyroxine, thyromimetic agents,dehydroepiandrosterones or analogs thereof, glucocorticoid receptoragonists or antagonists, orexin receptor antagonists, urocortin bindingprotein antagonists, glucagon-like peptide-1 receptor agonists, ciliaryneurotrophic factors (e.g., Axokine™), human agouti-related proteins(AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonistsor inverse agonists, neuromedin U receptor agonists, and the like.

Rimonabant (SR141716A also known under the tradename Accomplia™available from Sanofi-Synthelabo) can be prepared as described in U.S.Pat. No. 5,624,941. Other suitable CB-1 antagonists include thosedescribed in U.S. Pat. Nos. 5,747,524, 6,432,984 and 6,518,264; U.S.Patent Publication Nos. US2004/0092520, US2004/0157839, US200410214855,and US2004/0214838; U.S. patent application Ser. No. 10/971,599 filed onOct. 22, 2004; and PCT Patent Publication Nos. WO 02/076949, WO03/075660, WO04/048317, WO04/013120, and WO 04/012671.

Preferred apolipoprotein-B secretion/microsomal triglyceride transferprotein (apo-B/MTP) inhibitors for use as anti-obesity agents aregut-selective MTP inhibitors, such as dirlotapide described in U.S. Pat.No. 6,720,351;4-(4-(4-(4-((2-((4-methyl-4H-1,2,4-triazol-3-ylthio)methyl)-2-(4-chlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-sec-butyl-2H-1,2,4-triazol-3(4H)-one(R103757) described in U.S. Pat. Nos. 5,521,186 and 5,929,075; andimplitapide (BAY 13-9952) described in U.S. Pat. No. 6,265,431. As usedherein, the term “gut-selective” means that the MTP inhibitor has ahigher exposure to the gastrointestinal tissues versus systemicexposure.

Any thyromimetic can be used as the second agent in combination with acompound of the present invention. Such thyromimetic activity is readilydetermined by those skilled in the art according to standard assays(e.g., Atherosclerosis (1996) 126: 53-63). A variety of thyromimeticagents are known to those skilled in the art, for example thosedisclosed in U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; 5,061,798;5,284,971; 5,401,772; 5,654,468; and 5,569,674. Other antiobesity agentsinclude sibutramine which can be prepared as described in U.S. Pat. No.4,929,629. and bromocriptine which can be prepared as described in U.S.Pat. Nos. 3,752,814 and 3,752,888.

The compounds of the present invention can also be used in combinationwith other antihypertensive agents. Any anti-hypertensive agent can beused as the second agent in such combinations and examples are providedherein. Such antihypertensive activity is readily determined by thoseskilled in the art according to standard assays (e.g., blood pressuremeasurements).

Examples of presently marketed products containing antihypertensiveagents include calcium channel blockers, such as Cardizem®, Adalat®,Calan®, Cardene®, Covera®, Dilacor®, DynaCirc®, Procardia XL®, Sular®,Tiazac®, Vascor®, Verelan®, Isoptin®, Nimotop®, Norvasc®, and Plendil®;angiotensin converting enzyme (ACE) inhibitors, such as Accupril®,Altace®, Captopril®, Lotensin®, Mavik®, Monopril®, Prinivil®, Univasc®,Vasotec® and Zestril®.

Amlodipine and related dihydropyridine compounds are disclosed in U.S.Pat. No. 4,572,909, which is incorporated herein by reference, as potentanti-ischemic and antihypertensive agents. U.S. Pat. No. 4,879,303,which is incorporated herein by reference, discloses amlodipinebenzenesulfonate salt (also termed amlodipine besylate). Amlodipine andamlodipine besylate are potent and long lasting calcium channelblockers. As such, amlodipine, amlodipine besylate, amlodipine maleateand other pharmaceutically acceptable acid addition salts of amlodipinehave utility as antihypertensive agents and as antiischemic agents.Amlodipine besylate is currently sold as Norvasc®. Amlodipine has theformula

Calcium channel blockers which are within the scope of this inventioninclude, but are not limited to: bepridil, which may be prepared asdisclosed in U.S. Pat. No. 3,962,238 or U.S. Reissue No. 30,577;clentiazem, which may be prepared as disclosed in U.S. Pat. No.4,567,175; diltiazem, which may be prepared as disclosed in U.S. Pat.No. 3,562, fendiline, which may be prepared as disclosed in U.S. Pat.No. 3,262,977; gallopamil, which may be prepared as disclosed in U.S.Pat. No. 3,261,859; mibefradil, which may be prepared as disclosed inU.S. Pat. No. 4,808,605; prenylamine, which may be prepared as disclosedin U.S. Pat. No. 3,152,173; semotiadil, which may be prepared asdisclosed in U.S. Pat. No. 4,786,635; terodiline, which may be preparedas disclosed in U.S. Pat. No. 3,371,014; verapamil, which may beprepared as disclosed in U.S. Pat. No. 3,261,859; aranipine, which maybe prepared as disclosed in U.S. Pat. No. 4,572,909; barnidipine, whichmay be prepared as disclosed in U.S. Pat. No. 4,220,649; benidipine,which may be prepared as disclosed in European Patent ApplicationPublication No. 106,275; cilnidipine, which may be prepared as disclosedin U.S. Pat. No. 4,672,068; efonidipine, which may be prepared asdisclosed in U.S. Pat. No. 4,885,284; elgodipine, which may be preparedas disclosed in U.S. Pat. No. 4,952,592; felodipine, which may beprepared as disclosed in U.S. Pat. No. 4,264,611; isradipine, which maybe prepared as disclosed in U.S. Pat. No. 4,466,972; lacidipine, whichmay be prepared as disclosed in U.S. Pat. No. 4,801,599; lercanidipine,which may be prepared as disclosed in U.S. Pat. No. 4,705,797;manidipine, which may be prepared as disclosed in U.S. Pat. No.4,892,875; nicardipine, which may be prepared as disclosed in U.S. Pat.No. 3,985,758; nifedipine, which may be prepared as disclosed in U.S.Pat. No. 3,485,847; nilvadipine, which may be prepared as disclosed inU.S. Pat. No. 4,338,322; nimodipine, which may be prepared as disclosedin U.S. Pat. No. 3,799,934; nisoldipine, which may be prepared asdisclosed in U.S. Pat. No. 4,154,839; nitrendipine, which may beprepared as disclosed in U.S. Pat. No. 3,799,934; cinnarizine, which maybe prepared as disclosed in U.S. Pat. No. 2,882,271; flunarizine, whichmay be prepared as disclosed in U.S. Pat. No. 3,773,939; lidoflazine,which may be prepared as disclosed in U.S. Pat. No. 3,267,104;lomerizine, which may be prepared as disclosed in U.S. Pat. No.4,663,325; bencyclane, which may be prepared as disclosed in HungarianPatent No. 151,865; etafenone, which may be prepared as disclosed inGerman Patent No. 1,265,758; and perhexiline, which may be prepared asdisclosed in British Patent No. 1,025,578. The disclosures of all suchU.S. Patents are incorporated herein by reference.

Angiotensin Converting Enzyme Inhibitors (ACE-Inhibitors) which arewithin the scope of this invention include, but are not limited to:alacepril, which may be prepared as disclosed in U.S. Pat. No.4,248,883; benazepril, which may be prepared as disclosed in U.S. Pat.No. 4,410,520; captopril, which may be prepared as disclosed in U.S.Pat. Nos. 4,046,889 and 4,105,776; ceronapril, which may be prepared asdisclosed in U.S. Pat. No. 4,452,790; delapril, which may be prepared asdisclosed in U.S. Pat. No. 4,385,051; enalapril, which may be preparedas disclosed in U.S. Pat. No. 4,374,829; fosinopril, which may beprepared as disclosed in U.S. Pat. No. 4,337,201; imadapril, which maybe prepared as disclosed in U.S. Pat. No. 4,508,727; lisinopril, whichmay be prepared as disclosed in U.S. Pat. No. 4,555,502; moveltopril,which may be prepared as disclosed in Belgian Patent No. 893,553;perindopril, which may be prepared as disclosed in U.S. Pat. No.4,508,729; quinapril, which may be prepared as disclosed in U.S. Pat.No. 4,344,949; ramipril, which may be prepared as disclosed in U.S. Pat.No. 4,587,258; spirapril, which may be prepared as disclosed in U.S.Pat. No. 4,470,972; temocapril, which may be prepared as disclosed inU.S. Pat. No. 4,699,905; and trandolapril, which may be prepared asdisclosed in U.S. Pat. No. 4,933,361. The disclosures of all such U.S.patents are incorporated herein by reference.

Angiotensin-II receptor antagonists (A-II antagonists) which are withinthe scope of this invention include, but are not limited to:candesartan, which may be prepared as disclosed in U.S. Pat. No.5,196,444; eprosartan, which may be prepared as disclosed in U.S. Pat.No. 5,185,351; irbesartan, which may be prepared as disclosed in U.S.Pat. No. 5,270,317; losartan, which may be prepared as disclosed in U.S.Pat. No. 5,138,069; and valsartan, which may be prepared as disclosed inU.S. Pat. No. 5,399,578. The disclosures of all such U.S. patents areincorporated herein by reference.

Beta-adrenergic receptor blockers (beta- or β-blockers) which are withinthe scope of this invention include, but are not limited to: acebutolol,which may be prepared as disclosed in U.S. Pat. No. 3,857,952;alprenolol, which may be prepared as disclosed in Netherlands PatentApplication No. 6,605,692; amosulalol, which may be prepared asdisclosed in U.S. Pat. No. 4,217,305; arotinolol, which may be preparedas disclosed in U.S. Pat. No. 3,932,400; atenolol, which may be preparedas disclosed in U.S. Pat. No. 3,663,607 or 3,836,671; befunolol, whichmay be prepared as disclosed in U.S. Pat. No. 3,853,923; betaxolol,which may be prepared as disclosed in U.S. Pat. No. 4,252,984;bevantolol, which may be prepared as disclosed in U.S. Pat. No.3,857,981; bisoprolol, which may be prepared as disclosed in U.S. Pat.No. 4,171,370; bopindolol, which may be prepared as disclosed in U.S.Pat. No. 4,340,541; bucumolol, which may be prepared as disclosed inU.S. Pat. No. 3,663,570; bufetolol, which may be prepared as disclosedin U.S. Pat. No. 3,723,476; bufuralol, which may be prepared asdisclosed in U.S. Pat. No. 3,929,836; bunitrolol, which may be preparedas disclosed in U.S. Pat. Nos. 3,940,489 and 3,961,071; buprandolol,which may be prepared as disclosed in U.S. Pat. No. 3,309,406;butiridine hydrochloride, which may be prepared as disclosed in FrenchPatent No. 1,390,056; butofilolol, which may be prepared as disclosed inU.S. Pat. No. 4,252,825; carazolol, which may be prepared as disclosedin German Patent No. 2,240,599; carteolol, which may be prepared asdisclosed in U.S. Pat. No. 3,910,924; carvedilol, which may be preparedas disclosed in U.S. Pat. No. 4,503,067; celiprolol, which may beprepared as disclosed in U.S. Pat. No. 4,034,009; cetamolol, which maybe prepared as disclosed in U.S. Pat. No. 4,059,622; cloranolol, whichmay be prepared as disclosed in German Patent No. 2,213,044; dilevalol,which may be prepared as disclosed in Clifton et al., Journal ofMedicinal Chemistry, 1982, 25, 670; epanolol, which may be prepared asdisclosed in European Patent Publication Application No. 41,491;indenolol, which may be prepared as disclosed in U.S. Pat. No.4,045,482; labetalol, which may be prepared as disclosed in U.S. Pat.No. 4,012,444; levobunolol, which may be prepared as disclosed in U.S.Pat. No. 4,463,176; mepindolol, which may be prepared as disclosed inSeeman et al., Helv. Chim. Acta, 1971, 54, 241; metipranolol, which maybe prepared as disclosed in Czechoslovakian Patent Application No.128,471; metoprolol, which may be prepared as disclosed in U.S. Pat. No.3,873,600; moprolol, which may be prepared as disclosed in U.S. Pat. No.3,501,769I; nadolol, which may be prepared as disclosed in U.S. Pat. No.3,935,267; nadoxolol, which may be prepared as disclosed in U.S. Pat.No. 3,819,702; nebivalol, which may be prepared as disclosed in U.S.Pat. No. 4,654,362; nipradilol, which may be prepared as disclosed inU.S. Pat. No. 4,394,382; oxprenolol, which may be prepared as disclosedin British Patent No. 1,077,603; perbutolol, which may be prepared asdisclosed in U.S. Pat. No. 3,551,493; pindolol, which may be prepared asdisclosed in Swiss Patent Nos. 469,002 and 472,404; practolol, which maybe prepared as disclosed in U.S. Pat. No. 3,408,387; pronethalol, whichmay be prepared as disclosed in British Patent No. 909,357; propranolol,which may be prepared as disclosed in U.S. Pat. Nos. 3,337,628 and3,520,919; sotalol, which may be prepared as disclosed in Uloth et al.,Journal of Medicinal Chemistry, 1966, 9, 88; sufinalol, which may beprepared as disclosed in German Patent No. 2,728,641; talindol, whichmay be prepared as disclosed in U.S. Pat. Nos. 3,935,259 and 4,038,313;tertatolol, which may be prepared as disclosed in U.S. Pat. No.3,960,891; tilisolol, which may be prepared as disclosed in U.S. Pat.No. 4,129,565; timolol, which may be prepared as disclosed in U.S. Pat.No. 3,655,663; toliprolol, which may be prepared as disclosed in U.S.Pat. No. 3,432,545; and xibenolol, which may be prepared as disclosed inU.S. Pat. No. 4,018,824. The disclosures of all such U.S. patents areincorporated herein by reference.

Alpha-adrenergic receptor blockers (alpha- or α-blockers) which arewithin the scope of this invention include, but are not limited to:amosuialol, which may be prepared as disclosed in U.S. Pat. No.4,217,307; arotinolol, which may be prepared as disclosed in U.S. Pat.No. 3,932,400; dapiprazole, which may be prepared as disclosed in U.S.Pat. No. 4,252,721; doxazosin, which may be prepared as disclosed inU.S. Pat. No. 4,188,390; fenspiride, which may be prepared as disclosedin U.S. Pat. No. 3,399,192; indoramin, which may be prepared asdisclosed in U.S. Pat. No. 3,527,761; labetolol; naftopidil, which maybe prepared as disclosed in U.S. Pat. No. 3,997,666; nicergoline, whichmay be prepared as disclosed in U.S. Pat. No. 3,228,943; prazosin, whichmay be prepared as disclosed in U.S. Pat. No. 3,511,836; tamsulosin,which may be prepared as disclosed in U.S. Pat. No. 4,703,063;tolazoline, which may be prepared as disclosed in U.S. Pat. No.2,161,938; trimazosin, which may be prepared as disclosed in U.S. Pat.No. 3,669,968; and yohimbine, which may be isolated from natural sourcesaccording to methods well known to those skilled in the art. Thedisclosures of all such U.S. patents are incorporated herein byreference.

The term “vasodilator,” where used herein, is meant to include cerebralvasodilators, coronary vasodilators and peripheral vasodilators.Cerebral vasodilators within the scope of this invention include, butare not limited to: bencyclane; cinnarizine; citicoline, which may beisolated from natural sources as disclosed in Kennedy et al., Journal ofthe American Chemical Society, 1955, 77, 250 or synthesized as disclosedin Kennedy, Journal of Biological Chemistry, 1956, 222, 185;cyclandelate, which may be prepared as disclosed in U.S. Pat. No.3,663,597; ciclonicate, which may be prepared as disclosed in GermanPatent No. 1,910,481; diisopropylamine dichloroacetate, which may beprepared as disclosed in British Patent No. 862,248; eburnamonine, whichmay be prepared as disclosed in Hermann et al., Journal of the AmericanChemical Society, 1979, 101, 1540; fasudil, which may be prepared asdisclosed in U.S. Pat. No. 4,678,783; fenoxedil, which may be preparedas disclosed in U.S. Pat. No. 3,818,021; flunarizine, which may beprepared as disclosed in U.S. Pat. No. 3,773,939; ibudilast, which maybe prepared as disclosed in U.S. Pat. No. 3,850,941; ifenprodil, whichmay be prepared as disclosed in U.S. Pat. No. 3,509,164; lomerizine,which may be prepared as disclosed in U.S. Pat. No. 4,663,325; nafronyl,which may be prepared as disclosed in U.S. Pat. No. 3,334,096;nicametate, which may be prepared as disclosed in Blicke et al., Journalof the American Chemical Society, 1942, 64, 1722; nicergoline, which maybe prepared as disclosed above; nimodipine, which may be prepared asdisclosed in U.S. Pat. No. 3,799,934; papaverine, which may be preparedas reviewed in Goldberg, Chem. Prod. Chem. News, 1954, 17, 371;pentifylline, which may be prepared as disclosed in German Patent No.860,217; tinofedrine, which may be prepared as disclosed in U.S. Pat.No. 3,563,997; vincamine, which may be prepared as disclosed in U.S.Pat. No. 3,770,724; vinpocetine, which may be prepared as disclosed inU.S. Pat. No. 4,035,750; and viquidil, which may be prepared asdisclosed in U.S. Pat. No. 2,500,444. The disclosures of all such U.S.patents are incorporated herein by reference.

Coronary vasodilators within the scope of this invention include, butare not limited to: amotriphene, which may be prepared as disclosed inU.S. Pat. No. 3,010,965; bendazol, which may be prepared as disclosed inJ. Chem. Soc. 1958, 2426; benfurodil hemisuccinate, which may beprepared as disclosed in U.S. Pat. No. 3,355,463; benziodarone, whichmay be prepared as disclosed in U.S. Pat. No. 3,012,042; chloracizine,which may be prepared as disclosed in British Patent No. 740,932;chromonar, which may be prepared as disclosed in U.S. Pat. No.3,282,938; clobenfural, which may be prepared as disclosed in BritishPatent No. 1,160,925; clonitrate, which may be prepared from propanediolaccording to methods well known to those skilled in the art, e.g., seeAnnalen, 1870, 155, 165; cloricromen, which may be prepared as disclosedin U.S. Pat. No. 4,452,811; dilazep, which may be prepared as disclosedin U.S. Pat. No. 3,532,685; dipyridamole, which may be prepared asdisclosed in British Patent No. 807,826; droprenilamine, which may beprepared as disclosed in German Patent No. 2,521,113, efloxate, whichmay be prepared as disclosed in British Patent Nos. 803,372 and 824,547;erythrityl tetranitrate, which may be prepared by nitration oferythritol according to methods well-known to those skilled in the art;etafenone, which may be prepared as disclosed in German Patent No.1,265,758; fendiline, which may be prepared as disclosed in U.S. Pat.No. 3,262,977; floredil, which may be prepared as disclosed in GermanPatent No. 2,020,464; ganglefene, which may be prepared as disclosed inU.S.S.R. Patent No. 115,905; hexestrol, which may be prepared asdisclosed in U.S. Pat. No. 2,357,985; hexobendine, which may be preparedas disclosed in U.S. Pat. No. 3,267,103; itramin tosylate, which may beprepared as disclosed in Swedish Patent No. 168,308; khellin, which maybe prepared as disclosed in Baxter et al., Journal of the ChemicalSociety, 1949, S 30; lidoflazine, which may be prepared as disclosed inU.S. Pat. No. 3,267,104; mannitol hexanitrate, which may be prepared bythe nitration of mannitol according to methods well-known to thoseskilled in the art; medibazine, which may be prepared as disclosed inU.S. Pat. No. 3,119,826; nitroglycerin; pentaerythritol tetranitrate,which may be prepared by the nitration of pentaerythritol according tomethods well-known to those skilled in the art; pentrinitrol, which maybe prepared as disclosed in German Patent No. 638,422-3; perhexilline,which may be prepared as disclosed above; pimefylline, which may beprepared as disclosed in U.S. Pat. No. 3,350,400; prenylamine, which maybe prepared as disclosed in U.S. Pat. No. 3,152,173; propatyl nitrate,which may be prepared as disclosed in French Patent No. 1,103,113;trapidil, which may be prepared as disclosed in East German Patent No.55,956; tricromyl, which may be prepared as disclosed in U.S. Pat. No.2,769,015; trimetazidine, which may be prepared as disclosed in U.S.Pat. No. 3,262,852; trolnitrate phosphate, which may be prepared bynitration of triethanolamine followed by precipitation with phosphoricacid according to methods well-known to those skilled in the art;visnadine, which may be prepared as disclosed in U.S. Pat. Nos.2,816,118 and 2,980,699. The disclosures of all such U.S. patents areincorporated herein by reference.

Peripheral vasodilators within the scope of this invention include, butare not limited to: aluminum nicotinate, which may be prepared asdisclosed in U.S. Pat. No. 2,970,082; bamethan, which may be prepared asdisclosed in Corrigan et al., Journal of the American Chemical Society,1945, 67, 1894; bencyclane, which may be prepared as disclosed above;betahistine, which may be prepared as disclosed in Walter et al.;Journal of the American Chemical Society, 1941, 63, 2771; bradykinin,which may be prepared as disclosed in Hamburg et al., Arch. Biochem.Biophys., 1958, 76, 252; brovincamine, which may be prepared asdisclosed in U.S. Pat. No. 4,146,643; bufeniode, which may be preparedas disclosed in U.S. Pat. No. 3,542,870; buflomedil, which may beprepared as disclosed in U.S. Pat. No. 3,895,030; butalamine, which maybe prepared as disclosed in U.S. Pat. No. 3,338,899; cetiedil, which maybe prepared as disclosed in French Patent Nos. 1,460,571; ciclonicate,which may be prepared as disclosed in German Patent No. 1,910,481;cinepazide, which may be prepared as disclosed in Belgian Patent No.730,345; cinnarizine, which may be prepared as disclosed above;cyclandelate, which may be prepared as disclosed above; diisopropylaminedichloroacetate, which may be prepared as disclosed above; eledoisin,which may be prepared as disclosed in British Patent No. 984,810;fenoxedil, which may be prepared as disclosed above; flunarizine, whichmay be prepared as disclosed above; hepronicate, which may be preparedas disclosed in U.S. Pat. No. 3,384,642; ifenprodil, which may beprepared as disclosed above; iloprost, which may be prepared asdisclosed in U.S. Pat. No. 4,692,464; inositol niacinate, which may beprepared as disclosed in Badgett et al., Journal of the AmericanChemical Society, 1947, 69, 2907; isoxsuprine, which may be prepared asdisclosed in U.S. Pat. No. 3,056,836; kallidin, which may be prepared asdisclosed in Biochem. Biophys. Res. Commun., 1961, 6, 210; kallikrein,which may be prepared as disclosed in German Patent No. 1,102,973;moxisylyte, which may be prepared as disclosed in German Patent No.905,738; nafronyl, which may be prepared as disclosed above; nicametate,which may be prepared as disclosed above; nicergoline, which may beprepared as disclosed above; nicofuranose, which may be prepared asdisclosed in Swiss Patent No. 366,523; nylidrin, which may be preparedas disclosed in U.S. Pat. Nos. 2,661,372 and 2,661,373; pentifylline,which may be prepared as disclosed above; pentoxifylline, which may beprepared as disclosed in U.S. Pat. No. 3,422,107; piribedil, which maybe prepared as disclosed in U.S. Pat. No. 3,299,067; prostaglandin E₁,which may be prepared by any of the methods referenced in the MerckIndex, Twelfth Edition, Budaveri, Ed., New Jersey, 1996, p. 1353;suloctidil, which may be prepared as disclosed in German Patent No.2,334,404; tolazoline, which may be prepared as disclosed in U.S. Pat.No. 2,161,938; and xanthinol niacinate, which may be prepared asdisclosed in German Patent No. 1,102,750 or Korbonits et al., Acta.Pharm. Hung., 1968, 38, 98. The disclosures of all such U.S. patents areincorporated herein by reference.

The term “diuretic,” within the scope of this invention, is meant toinclude diuretic benzothiadiazine derivatives, diureticorganomercurials, diuretic purines, diuretic steroids, diureticsulfonamide derivatives, diuretic uracils and other diuretics such asamanozine, which may be prepared as disclosed in Austrian Patent No.168,063; amiloride, which may be prepared as disclosed in Belgian PatentNo. 639,386; arbutin, which may be prepared as disclosed inTschitschibabin, Annalen, 1930, 479, 303; chlorazanil, which may beprepared as disclosed in Austrian Patent No. 168,063; ethacrynic acid,which may be prepared as disclosed in U.S. Pat. No. 3,255,241; etozolin,which may be prepared as disclosed in U.S. Pat. No. 3,072,653;hydracarbazine, which may be prepared as disclosed in British Patent No.856,409; isosorbide, which may be prepared as disclosed in U.S. Pat. No.3,160,641; mannitol; metochalcone, which may be prepared as disclosed inFreudenberg et al., Ber., 1957, 90, 957; muzolimine, which may beprepared as disclosed in U.S. Pat. No. 4,018,890; perhexiline, which maybe prepared as disclosed above; ticrynafen, which may be prepared asdisclosed in U.S. Pat. No. 3,758,506; triamterene which may be preparedas disclosed in U.S. Pat. No. 3,081,230; and urea. The disclosures ofall such U.S. patents are incorporated herein by reference.

Diuretic benzothiadiazine derivatives within the scope of this inventioninclude, but are not limited to: althiazide, which may be prepared asdisclosed in British Patent No. 902,658; bendroflumethiazide, which maybe prepared as disclosed in U.S. Pat. No. 3,265,573; benzthiazide,McManus et al., 136th Am. Soc. Meeting (Atlantic City, September 1959),Abstract of papers, pp 13-O; benzylhydrochlorothiazide, which may beprepared as disclosed in U.S. Pat. No. 3,108,097; buthiazide, which maybe prepared as disclosed in British Patent Nos. 861,367 and 885,078;chlorothiazide, which may be prepared as disclosed in U.S. Pat. Nos.2,809,194 and 2,937,169; chlorthalidone, which may be prepared asdisclosed in U.S. Pat. No. 3,055,904; cyclopenthiazide, which may beprepared as disclosed in Belgian Patent No. 587,225; cyclothiazide,which may be prepared as disclosed in Whitehead et al., Journal ofOrganic Chemistry, 1961, 26, 2814; epithiazide, which may be prepared asdisclosed in U.S. Pat. No. 3,009,911; ethiazide, which may be preparedas disclosed in British Patent No. 861,367; fenquizone, which may beprepared as disclosed in U.S. Pat. No. 3,870,720; indapamide, which maybe prepared as disclosed in U.S. Pat. No. 3,565,911;hydrochlorothiazide, which may be prepared as disclosed in U.S. Pat. No.3,164,588; hydroflumethiazide, which may be prepared as disclosed inU.S. Pat. No. 3,254,076; methyclothiazide, which may be prepared asdisclosed in Close et al., Journal of the American Chemical Society,1960, 82, 1132; meticrane, which may be prepared as disclosed in FrenchPatent Nos. M2790 and 1,365,504; metolazone, which may be prepared asdisclosed in U.S. Pat. No. 3,360,518; paraflutizide, which may beprepared as disclosed in Belgian Patent No. 620,829; polythiazide, whichmay be prepared as disclosed in U.S. Pat. No. 3,009,911; quinethazone,which may be prepared as disclosed in U.S. Pat. No. 2,976,289;teclothiazide, which may be prepared as disclosed in Close et al.,Journal of the American Chemical Society, 1960, 82, 1132; andtrichlormethiazide, which may be prepared as disclosed in deStevens etal., Experientia, 1960, 16, 113. The disclosures of all such U.S.patents are incorporated herein by reference.

Diuretic sulfonamide derivatives within the scope of this inventioninclude, but are not limited to: acetazolamide, which may be prepared asdisclosed in U.S. Pat. No. 2,980,679; ambuside, which may be prepared asdisclosed in U.S. Pat. No. 3,188,329; azosemide, which may be preparedas disclosed in U.S. Pat. No. 3,665,002; bumetanide, which may beprepared as disclosed in U.S. Pat. No. 3,634,583; butazolamide, whichmay be prepared as disclosed in British Patent No. 769,757;chloraminophenamide, which may be prepared as disclosed in U.S. Pat.Nos. 2,809,194, 2,965,655 and 2,965,656; clofenamide, which may beprepared as disclosed in Olivier, Rec. Trav. Chim., 1918, 37, 307;clopamide, which may be prepared as disclosed in U.S. Pat. No.3,459,756; clorexolone, which may be prepared as disclosed in U.S. Pat.No. 3,183,243; disulfamide, which may be prepared as disclosed inBritish Patent No. 851,287; ethoxolamide, which may be prepared asdisclosed in British Patent No. 795,174; furosemide, which may beprepared as disclosed in U.S. Pat. No. 3,058,882; mefruside, which maybe prepared as disclosed in U.S. Pat. No. 3,356,692; methazolamide,which may be prepared as disclosed in U.S. Pat. No. 2,783,241;piretanide, which may be prepared as disclosed in U.S. Pat. No.4,010,273; torasemide, which may be prepared as disclosed in U.S. Pat.No. 4,018,929; tripamide, which may be prepared as disclosed in JapanesePatent No. 73 05,585; and xipamide, which may be prepared as disclosedin U.S. Pat. No. 3,567,777. The disclosures of all such U.S. patents areincorporated herein by reference.

Osteoporosis is a systemic skeletal disease, characterized by low bonemass and deterioration of bone tissue, with a consequent increase inbone fragility and susceptibility to fracture. In the U.S., thecondition affects more than 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. Hip fractures are the most seriousconsequence of osteoporosis, with 5-20% of patients dying within oneyear, and over 50% of survivors being incapacitated.

The elderly are at greatest risk of osteoporosis, and the problem istherefore predicted to increase significantly with the aging of thepopulation. Worldwide fracture incidence is forecasted to increasethreefold over the next 60 years, and one study has estimated that therewill be 4.5 million hip fractures worldwide in 2050.

Women are at greater risk of osteoporosis than men. Women experience asharp acceleration of bone loss during the five years followingmenopause. Other factors that increase the risk include smoking, alcoholabuse, a sedentary lifestyle and low calcium intake.

Those skilled in the art will recognize that anti-resorptive agents (forexample progestins, polyphosphonates, bisphosphonate(s), estrogenagonists/antagonists, estrogen, estrogen/progestin combinations,Premarin®, estrone, estriol or 17α- or 17β-ethynyl estradiol) may beused in conjunction with the compounds of the present invention.

Exemplary progestins are available from commercial sources and include:algestone acetophenide, altrenogest, amadinone acetate, anagestoneacetate, chlormadinone acetate, cingestol, clogestone acetate,clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone,dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel,flurogestone acetate, gestaclone, gestodene, gestonorone caproate,gestrinone, haloprogesterone, hydroxyprogesterone caproate,levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate,melengestrol acetate, methynodiol diacetate, norethindrone,norethindrone acetate, norethynodrel, norgestimate, norgestomet,norgestrel, oxogestone phenpropionate, progesterone, quingestanolacetate, quingestrone, and tigestol.

Preferred progestins are medroxyprogestrone, norethindrone andnorethynodrel.

Exemplary bone resorption inhibiting polyphosphonates includepolyphosphonates of the type disclosed in U.S. Pat. No. 3,683,080, thedisclosure of which is incorporated herein by reference. Preferredpolyphosphonates are geminal diphosphonates (also referred to asbis-phosphonates). Tiludronate disodium is an especially preferredpolyphosphonate. Ibandronic acid is an especially preferredpolyphosphonate. Alendronate and resindronate are especially preferredpolyphosphonates. Zoledronic acid is an especially preferredpolyphosphonate. Other preferred polyphosphonates are6-amino-1-hydroxy-hexylidene-bisphosphonic acid and1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid. Thepolyphosphonates may be administered in the form of the acid, or of asoluble alkali metal salt or alkaline earth metal salt. Hydrolyzableesters of the polyphosphonates are likewise included. Specific examplesinclude ethane-1-hydroxy 1,1-diphosphonic acid, methane diphosphonicacid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichlorodiphosphonic acid, methane hydroxy diphosphonic acid,ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonicacid, propane-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-3,3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenylamino methane diphosphonic acid, N,N-dimethylamino methane diphosphonicacid, N(2-hydroxyethyl) amino methane diphosphonic acid,butane-4-amino-1-hydroxy-1,1-diphosphonic acid,pentane-5-amino-1-hydroxy-1,1-diphosphonic acid,hexane-6-amino-1-hydroxy-1,1-diphosphonic acid and pharmaceuticallyacceptable esters and salts thereof.

In particular, the compounds of this invention may be combined with amammalian estrogen agonist/antagonist. Any estrogen agonist/antagonistmay be used in the combination aspect of this invention. The termestrogen agonist/antagonist refers to compounds which bind with theestrogen receptor, inhibit bone turnover and/or prevent bone loss. Inparticular, estrogen agonists are herein defined as chemical compoundscapable of binding to the estrogen receptor sites in mammalian tissue,and mimicking the actions of estrogen in one or more tissue. Estrogenantagonists are herein defined as chemical compounds capable of bindingto the estrogen receptor sites in mammalian tissue, and blocking theactions of estrogen in one or more tissues. Such activities are readilydetermined by those skilled in the art of standard assays includingestrogen receptor binding assays, standard bone histomorphometric anddensitometer methods, and Eriksen E. F. et al., Bone Histomorphometry,Raven Press, New York, 1994, pages 1-74; Grier S. J. et. al., The Use ofDual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996,31(1):50-62; Wahner H. W. and Fogelman I., The Evaluation ofOsteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice.,Martin Dunitz Ltd., London 1994, pages 1-296). A variety of thesecompounds are described and referenced below.

Another preferred estrogen agonist/antagonist is3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid, which is disclosedin Willson et al., Endocrinology, 1997, 138, 3901-3911.

Another preferred estrogen agonist/antagonist is tamoxifen:(ethanamine,2-(-4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl, (Z)-2-,2-hydroxy-1,2,3-propanetricarboxylate(1:1)) and related compounds whichare disclosed in U.S. Pat. No. 4,536,516, the disclosure of which isincorporated herein by reference.

Another related compound is 4-hydroxy tamoxifen, which is disclosed inU.S. Pat. No. 4,623,660, the disclosure of which is incorporated hereinby reference.

A preferred estrogen agonist/antagonist is raloxifene: (methanone,(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)-hydrochloride)which is disclosed in U.S. Pat. No. 4,418,068, the disclosure of whichis incorporated herein by reference.

Another preferred estrogen agonist/antagonist is toremifene:(ethanamine,2-(4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-,2-hydroxy-1,2,3-propanetricarboxylate (1:1) which is disclosed in U.S.Pat. No. 4,996,225, the disclosure of which is incorporated herein byreference.

Another preferred estrogen agonist/antagonist is centchroman:1-(2-((4-(-methoxy-2,2,dimethyl-3-phenyl-chroman-4-yl)-phenoxy)-ethyl)-pyrrolidine, which isdisclosed in U.S. Pat. No. 3,822,287, the disclosure of which isincorporated herein by reference. Also preferred is levormeloxifene.

Another preferred estrogen agonist/antagonist is idoxifene:(E)-1-(2-(4-(1-(4-iodo-phenyl)-2-phenylbut-1-enyl)-phenoxy)-ethyl)-pyrrolidinone,which is disclosed in U.S. Pat. No. 4,839,155, the disclosure of whichis incorporated herein by reference.

Another preferred estrogen agonist/antagonist is2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-ylethoxy)-phenoxy]-benzo[b]thiophen-6-olwhich is disclosed in U.S. Pat. No. 5,488,058, the disclosure of whichis incorporated herein by reference.

Another preferred estrogen agonist/antagonist is6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-ylethoxy)-benzyl)-naphthalen-2-ol,which is disclosed in U.S. Pat. No. 5,484,795, the disclosure of whichis incorporated herein by reference.

Another preferred estrogen agonist/antagonist is(4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)phenyl)-(6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl)-methanonewhich is disclosed, along with methods of preparation, in PCTpublication no. WO 95/10513 assigned to Pfizer Inc.

Other preferred estrogen agonist/antagonists include the compounds,TSE-424 (Wyeth-Ayerst Laboratories) and arazoxifene.

Other preferred estrogen agonist/antagonists include compounds asdescribed in commonly assigned U.S. Pat. No. 5,552,412, the disclosureof which is incorporated herein by reference. Especially preferredcompounds described therein are:

-   cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;-   (−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol    (also known as lasofoxifene);-   cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;-   cis-1-(6′-pyrrolodinoethoxy-3′-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;-   1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;-   cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;    and-   1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

Other estrogen agonist/antagonists are described in U.S. Pat. No.4,133,814 (the disclosure of which is incorporated herein by reference).U.S. Pat. No. 4,133,814 discloses derivatives of2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxide.

Other anti-osteoporosis agents, which can be used as the second agent incombination with a compound of the present invention, include, forexample, the following: parathyroid hormone (PTH) (a bone anabolicagent); parathyroid hormone (PTH) secretagogues (see, e.g., U.S. Pat.No. 6,132,774), particularly calcium receptor antagonists; calcitonin;and vitamin D and vitamin D analogs.

Any selective androgen receptor modulator (SARM) can be used incombination with a compound of the present invention. A selectiveandrogen receptor modulator (SARM) is a compound that possessesandrogenic activity and which exerts tissue-selective effects. SARMcompounds can function as androgen receptor agonists, partial agonists,partial antagonists or antagonists. Examples of suitable SARMs includecompounds such as cyproterone acetate, chlormadinone, flutamide,hydroxyflutamide, bicalutamide, nilutamide, spironolactone,4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinoline derivatives,1,2-dihydropyridino [5,6-g]quinoline derivatives andpiperidino[3,2-g]quinolinone derivatives.

Cypterone, also known as (1b,2b)6-chloro-1,2-dihydro-17-hydroxy-3′H-cyclopropa[1,2]pregna-1,4,6-triene-3,20-dioneis disclosed in U.S. Pat. No. 3,234,093. Chlormadinone, also known as17-(acetyloxy)-6-chloropregna-4,6-diene-3,20-dione, in its acetate form,acts as an anti-androgen and is disclosed in U.S. Pat. No. 3,485,852.Nilutamide, also known as5,5-dimethyl-3-[4-nito-3-(trifluoromethyl)phenyl]-2,4-imidazolidinedioneand by the trade name Nilandron® is disclosed in U.S. Pat. No.4,097,578. Flutamide, also known as2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide and the tradename Eulexin® is disclosed in U.S. Pat. No. 3,847,988. Bicalutamide,also known as 4′-cyano-a′,a′,a′-trifluoro-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropiono-m-toluidideand the trade name Casodex® is disclosed in EP-100172. The enantiomersof biclutamide are discussed by Tucker and Chesterton, J. Med. Chem.1988, 31, 885-887. Hydroxyflutamide, a known androgen receptorantagonist in most tissues, has been suggested to function as a SARM foreffects on IL-6 production by osteoblasts as disclosed in Hofbauer etal. J. Bone Miner. Res. 1999, 14, 1330-1337. Additional SARMs have beendisclosed in U.S. Pat. No. 6,017,924; WO 01/16108, WO 01/16133, WO01/16139, WO 02/00617, WO 02/16310, U.S. Patent Application PublicationNo. US 2002/0099096, U.S. Patent Application Publication No. US2003/0022868, WO 03/1011302 and WO 03/011824. All of the abovereferences are hereby incorporated by reference herein.

The starting materials and reagents for the above described compounds,are also readily available or can be easily synthesized by those skilledin the art using conventional methods of organic synthesis. For example,many of the compounds used herein, are related to, or are derived fromcompounds in which there is a large scientific interest and commercialneed, and accordingly many such compounds are commercially available orare reported in the literature or are easily prepared from othercommonly available substances by methods which are reported in theliterature.

Some of the compounds of this invention or intermediates in theirsynthesis have asymmetric carbon atoms and therefore are enantiomers ordiastereomers. Diasteromeric mixtures can be separated into theirindividual diastereomers on the basis of their physical chemicaldifferences by methods known per se, for example, by chromatographyand/or fractional crystallization. Enantiomers can be separated by, forexample, chiral HPLC methods or converting the enantiomeric mixture intoa diastereomeric mixture by reaction with an appropriate opticallyactive compound (e.g., alcohol), separating the diastereomers andconverting (e.g., hydrolyzing) the individual diastereomers to thecorresponding pure enantiomers. Also, an enantiomeric mixture of thecompounds or an intermediate in their synthesis which contain an acidicor basic moiety may be separated into their corresponding pureenantiomers by forming a diastereomic salt with an optically pure chiralbase or acid (e.g., 1-phenyl-ethyl amine, dibenzyl tartrate or tartaricacid) and separating the diasteromers by fractional crystallizationfollowed by neutralization to break the salt, thus providing thecorresponding pure enantiomers. All such isomers, includingdiastereomers, enantiomers and mixtures thereof are considered as partof this invention for all of the compounds of the present invention,including the compounds of the present invention. Also, some of thecompounds of this invention are atropisomers (e.g., substituted biaryls)and are considered as part of this invention.

More specifically, the compounds of this invention may be obtained inenantiomerically enriched form by resolving the racemate of the finalcompound or an intermediate in its synthesis, employing chromatography(preferably high pressure liquid chromatography [HPLC]) on an asymmetricresin (preferably Chiralcel™ AD or OD (obtained from ChiralTechnologies, Exton, Pa.)) with a mobile phase consisting of ahydrocarbon (preferably heptane or hexane) containing between 0 and 50%isopropanol (preferably between 2 and 20%) and between 0 and 5% of analkyl amine (preferably 0.1% of diethylamine), Concentration of theproduct containing fractions affords the desired materials.

Some of the compounds of this invention are acidic and they form a saltwith a pharmaceutically acceptable cation. Some of the compounds of thisinvention are basic and they form a salt with a pharmaceuticallyacceptable anion. All such salts are within the scope of this inventionand they can be prepared by conventional methods such as combining theacidic and basic entities, usually in a stoichiometric ratio, in eitheran aqueous, non-aqueous or partially aqueous medium, as appropriate. Thesalts are recovered either by filtration, by precipitation with anon-solvent followed by filtration, by evaporation of the solvent, or,in the case of aqueous solutions, by lyophilization, as appropriate. Thecompounds can be obtained in crystalline form by dissolution in anappropriate solvent(s) such as ethanol, hexanes or water/ethanolmixtures.

In addition, when the compounds of this invention form hydrates orsolvates they are also within the scope of the invention.

The compounds of this invention, their prodrugs and the salts of suchcompounds and prodrugs are all adapted to therapeutic use as agents thatinhibit cholesterol ester transfer protein activity in mammals,particularly humans. Thus, the compounds of this invention elevateplasma HDL cholesterol, its associated components, and the functionsperformed by them in mammals, particularly humans. By virtue of theiractivity, these agents also reduce plasma levels of triglycerides, VLDLcholesterol, Apo-B, LDL cholesterol and their associated components inmammals, particularly humans. Moreover, these compounds are useful inequalizing LDL cholesterol and HDL cholesterol. Hence, these compoundsare useful for the treatment and correction of the various dyslipidemiasobserved to be associated with the development and incidence ofatherosclerosis and cardiovascular disease, including coronary arterydisease, coronary heart disease, coronary vascular disease, peripheralvascular disease, hypoalphalipoproteinemia, hyperbetalipoproteinemia,hypertriglyceridemia, hypercholesterolemia,familial-hypercholesterolemia, low HDL and associated components,elevated LDL and associated components, elevated Lp(a), elevatedsmall-dense LDL, elevated VLDL and associated components andpost-prandial lipemia.

Further, introduction of a functional CETP gene into an animal lackingCETP (mouse) results in reduced HDL levels (Agellon, L. B., et al: J.Biol. Chem. (1991) 266: 10796-10801.) and increased susceptibility toatherosclerosis. (Marotti, K. R., et al: Nature (1993) 364: 73-75.).Also, inhibition of CETP activity with an inhibitory antibody raisesHDL-cholesterol in hamster (Evans, G. F., et al: J. of Lipid Research(1994) 35: 1634-1645.) and rabbit (Whitlock, M. E., et al: J. Clin.Invest. (1989) 84: 129-137). Suppression of increased plasma CETP byintravenous injection with antisense oligodeoxynucleotides against CETPmRNA reduced atherosclerosis in cholesterol-fed rabbits (Sugano, M., etal: J. of Biol. Chem. (1998) 273: 5033-5036.) Importantly, humansubjects deficient in plasma CETP, due to a genetic mutation possessmarkedly elevated plasma HDL-cholesterol levels and apolipoprotein A-l,the major apoprotein component of HDL. In addition, most demonstratemarkedly decreased plasma LDL cholesterol and apolipoprotein B (themajor apolipoprotein component of LDL. (Inazu, A., Brown, M. L., Hester,C. B., et al.: N. Engl. J. Med. (1990) 323: 1234-1238.)

Given the negative correlation between the levels of HDL cholesterol andHDL associated lipoproteins, and the positive correlation betweentriglycerides, LDL cholesterol, and their associated apolipoproteins inblood with the development of cardiovascular, cerebral vascular andperipheral vascular diseases, the compounds of this invention, theirprodrugs and the salts of such compounds and prodrugs, by virtue oftheir pharmacologic action, are useful for the prevention, arrestmentand/or regression of atherosclerosis and its associated disease states.These include cardiovascular disorders (e.g., angina, ischemia, cardiacischemia and myocardial infarction), complications due to cardiovasculardisease therapies (e.g., reperfusion injury and angioplasticrestenosis), hypertension, elevated cardiovascular risk associated withhypertension, stroke, atherosclerosis associated with organtransplantation, cerebrovascular disease, cognitive dysfunction(including, but not limited to, dementia secondary to atherosclerosis,transient cerebral ischemic attacks, neurodegeneration, neuronaldeficient, and delayed onset or procession of Alzheimer's disease),elevated levels of oxidative stress, elevated levels of CReactiveProtein, Metabolic Syndrome and elevated levels of HbA1C.

Because of the beneficial effects widely associated with elevated HDLlevels, an agent which inhibits CETP activity in humans, by virtue ofits HDL increasing ability, also provides valuable avenues for therapyin a number of other disease areas as well.

Thus, given the ability of the compounds of this invention, theirprodrugs and the salts of such compounds and prodrugs to alterlipoprotein composition via inhibition of cholesterol ester transfer,they are of use in the treatment of vascular complications associatedwith diabetes, lipoprotein abnormalities associated with diabetes andsexual dysfunction associated with diabetes and vascular disease.Hyperlipidemia is present in most subjects with diabetes mellitus(Howard, B. V. 1987. J. Lipid Res. 28, 613). Even in the presence ofnormal lipid levels, diabetic subjects experience a greater risk ofcardiovascular disease (Kannel, W. B. and McGee, D. L. 1979. DiabetesCare 2, 120). CETP-mediated cholesteryl ester transfer is known to beabnormally increased in both insulin-dependent (Bagdade, J. D.,Subbaiah, P. V. and Ritter, M. C. 1991. Eur. J. Clin. Invest. 21, 161)and non-insulin dependent diabetes (Bagdade. J. D., Ritter, M. C., Lane,J. and Subbaiah. 1993. Atherosclerosis 104, 69). It has been suggestedthat the abnormal increase in cholesterol transfer results in changes inlipoprotein composition, particularly for VLDL and LDL, that are moreatherogenic (Bagdade, J. D., Wagner, J. D., Rudel, L. L., and Clarkson,T. B. 1995 J. Lipid Res. 36, 759). These changes would not necessarilybe observed during routine lipid screening. Thus the present inventionwill be useful in reducing the risk of vascular complications as aresult of the diabetic condition.

The described agents are useful in the treatment of obesity and elevatedcardiovascular risk associated with obesity. In both humans (Radeau, T.,Lau, P., Robb, M., McDonnell, M., Ailhaud, G. and McPherson, R., 1995.Journal of Lipid Research. 36 (12):2552-61) and nonhuman primates(Quinet, E., Tall, A., Ramakrishnan, R. and Rudel, L., 1991. Journal ofClinical Investigation. 87 (5):1559-66) mRNA for CETP is expressed athigh levels in adipose tissue. The adipose message increases with fatfeeding (Martin, L. J., Connelly, P. W., Nancoo, D., Wood, N., Zhang, Z.J., Maguire, G., Quinet, E., Tall, A. R., Marcel, Y. L. and McPherson,R., 1993. Journal of Lipid Research. 34 (3):437-46), and is translatedinto functional transfer protein and through secretion contributessignificantly to plasma CETP levels. In human adipocytes the bulk ofcholesterol is provided by plasma LDL and HDL (Fong, B. S., and Angel,A., 1989. Biochimica et Biophysica Acta. 1004 (1):53-60). The uptake ofHDL cholesteryl ester is dependent in large part on CETP (Benoist, F.,Lau, P., McDonnell, M., Doelle, H., Milne, R. and McPherson, R., 1997.Journal of Biological Chemistry. 272 (38):23572-7). This ability of CETPto stimulate HDL cholesteryl uptake, coupled with the enhanced bindingof HDL to adipocytes in obese subjects (Jimenez, J. G., Fong, B.,Julien, P., Despres, J. P., Rotstein, L., and Angel, A., 1989.International Journal of Obesity. 13 (5):699-709), suggests a role forCETP, not only in generating the low HDL phenotype for these subjects,but in the development of obesity itself by promoting cholesterolaccumulation. Inhibitors of CETP activity that block this processtherefore serve as useful adjuvants to dietary therapy in causing weightreduction.

CETP inhibitors are useful in the treatment of inflammation due toGram-negative sepsis and septic shock. For example, the systemictoxicity of Gram-negative sepsis is in large part due to endotoxin, alipopolysaccharide (LPS) released from the outer surface of thebacteria, which causes an extensive inflammatory response.Lipopolysaccharide can form complexes with lipoproteins (Ulevitch, R.J., Johnston, A. R., and Weinstein, D. B., 1981. J. Clin. Invest. 67,827-37). In vitro studies have demonstrated that binding of LPS to HDLsubstantially reduces the production and release of mediators ofinflammation (Ulevitch, R. J., Johhston, A. R., 1978. J. Clin. Invest.62, 1313-24). In vivo studies show that transgenic mice expressing humanapo-AI and elevated HDL levels are protected from septic shock (Levine,D. M., Parker, T. S., Donnelly, T. M., Walsh, A. M., and Rubin, A. L.1993. Proc. Natl. Acad. Sci. 90, 12040-44). Importantly, administrationof reconstituted HDL to humans challenged with endotoxin resulted in adecreased inflammatory response (Pajkrt, D., Doran, J. E., Koster, F.,Lerch, P. G., Arnet, B., van der Poll, T., ten Cate, J. W., and vanDeventer, S. J. H. 1996. J. Exp. Med. 184, 1601-08). The CETPinhibitors, by virtue of the fact that they raise HDL levels, attenuatethe development of inflammation and septic shock. These compounds wouldalso be useful in the treatment of endotoxemia, autoimmune diseases andother systemic disease indications, organ or tissue transplant rejectionand cancer.

The utility of the compounds of the invention, their prodrugs and thesalts of such compounds and prodrugs as medical agents in the treatmentof the above described disease/conditions in mammals (e.g. humans, maleor female) is demonstrated by the activity of the compounds of thisinvention in conventional assays and the in vitro assay described below.The in vivo assay (with appropriate modifications within the skill inthe art) may be used to determine the activity of other lipid ortriglyceride controlling agents as well as the compounds of thisinvention. Such assays also provide a means whereby the activities ofthe compounds of this invention, their prodrugs and the salts of suchcompounds and prodrugs (or the other agents described herein) can becompared to each other and with the activities of other known compounds.The results of these comparisons are useful for determining dosagelevels in mammals, including humans, for the treatment of such diseases.

The following protocols can of course be varied by those skilled in theart.

The hyperalphacholesterolemic activity of the compounds can bedetermined by assessing the effect of these compounds on the action ofcholesteryl ester transfer protein by measuring the relative transferratio of radiolabeled lipids between lipoprotein fractions, essentiallyas previously described by Morton in J. Biol. Chem. 256, 11992, 1981 andby Dias in Clin. Chem. 34, 2322, 1988.

CETP in Vitro Assay

The following is a brief description of assays of cholesteryl estertransfer in 97% (whole) or diluted human plasma (in vitro) and animalplasma (ex vivo): CETP activity in the presence or absence of drug isassayed by determining the transfer of ³H-labeled cholesteryl oleate(CO) from exogenous tracer HDL or LDL to the nonHDL or HDL lipoproteinfraction in human plasma, respectively, or from ³H-labeled LDL to theHDL fraction in animal plasma. Labeled human lipoprotein substrates areprepared similarly to the method described by Morton in which theendogenous CETP activity in plasma is employed to transfer ³H—CO fromphospholipid liposomes to all the lipoprotein fractions in plasma.³H-labeled LDL and HDL are subsequently isolated by sequentialultracentrifugation at the density cuts of 1.019-1.063 and 1.10-1.21g/ml, respectively.

For the 97% or whole plasma activity assay, ³H-labeled HDL is added toplasma at 10-25 nmoles CO/ml and the samples incubated at 37° C. for2.5-3 hrs. Non-HDL lipoproteins are then precipitated by the addition ofan equal volume of 20% (wt/vol) polyethylene glycol 8000 (Dias). Thesamples are centrifuged 750 g×20 minutes and the radioactivity containedin the HDL-containing supernatant determined by liquid scintillationcounting. Introducing varying quantities of the compounds of thisinvention as a solution in dimethylsulfoxide into human plasma, beforeaddition of the radiolabeled cholesteryl oleate, and comparing theamounts of radiolabel transferred compared to incubations containing noinhibitor compounds allows the cholesteryl ester transfer inhibitoryactivities to be determined.

When a more sensitive assay is desirable, an in vitro assay usingdiluted human plasma is utilized. For this assay, ³H-labeled LDL isadded to plasma at 50 nmoles CO/ml and the samples incubated at 37° C.for 7 hrs. Non-HDL lipoproteins are then precipitated by the addition ofpotassium phosphate to 100 mM final concentration followed by manganesechloride to 20 mM final concentration. After vortexing, the samples arecentrifuged 750 g×20 minutes and the radioactivity contained in theHDL-containing supernatant determined by liquid scintillation counting.Introducing varying quantities of the compounds of this invention as asolution in dimethylsulfoxide into diluted human plasma, before additionof the radiolabeled cholesteryl oleate, and comparing the amounts ofradiolabel transferred compared to incubations containing no inhibitorcompounds allows the cholesteryl ester transfer inhibitory activities tobe determined. This assay has been adapted to run in microtiter plateformat with liquid scintillation counting accomplished using a Wallacplate reader.

Alternatively, the CETP inhibitory activity of compounds can bedetermined using microtiter plate-based fluorescent transfer assayswhere the CETP-dependent transfer of a self-quenching cholesteryl esteranalog (Bodipy-CE) from human ApoAl-containing emulsion particles to theendogenous lipoproteins in plasma is monitored.

Fluorescent Bodipy-CE donors are prepared by drying down 14 mg of PC,1.6 mg triolein and 3.5 mg of BODIPY-CE at 60° C. in a vacuum oven andthen hydrating the lipids at 80° C. in 12 ml of PBS by probe sonication(at 25% of full power setting) for 2 min under a stream of N₂. The lipidmixture is then cooled to 45° C. and 5 mg (0.125 ?M) of humanapolipoprotein Al (from Biodesign, Saco Me.) is added, and againsonicated (at 25% of full power) for 20 min at 45° C., pausing aftereach minute to allow the probe to cool. The resulting emulsion is spunfor 30 min at 3000×g to remove metal probe fragments and then adjustedto 1.12 gm/ml with sodium bromide and layered below a solution of NaBr1.10 g/ml (16 ml) and subjected to density gradient ultracentrifugationfor 24 hours at 50,000-×g to remove unincorporated apolipoprotein Al andsmall dense particles that remain at the bottom of the gradient. Themore buoyant emulsion particles are collected from the top of thegradient and dialyzed in 6 liters (2 changes) of PBS/0.02% azide, anddiluted to the appropriate concentrations prior to use.

The CETP-dependent transfer of fluorescent CE analog is monitored inincubations containing the fluorescent human-apolipoproteinAl-containing donor particles, and a source of CETP and acceptorlipoproteins which in these cases are present in diluted human plasma.Bodipy CE fluorescence in the donor particles in the unincubated donorparticles is quenched, and the CETP-dependent transfer of Bodipy CE toacceptor particles results in an increase in fluorescence.

When a high sensitivity assay is desired, compounds in 100% dimethylsulfoxide are tested in a 2.5% plasma 384-well microtiter plate assay.One microliter of compound in 100% dimethyl sulfoxide is added to wellscontaining 20 ul of 3.75% human plasma (diluted with PBS) using aclonemaster solution transfer device. Transfer is initiated via theaddition of 10 ul of 7.5% donors (also diluted with PBS). Followingmixing, each plate is taped or placed in a Matripress plate stacker toavoid evaporation and incubated overnight at room temp. (16-20 hrs).Fluorescence is determined on a fluorescent plate reader, 485/530 nmfilters, 505 nm dichroic filter. Note that depending upon liquidhandling capabilities the intermediate dilutions of plasma andfluorescent donors and the aliquot size of those dilutions can beadjusted as necessary.

When a lower sensitivity assay is desired compounds are tested in a 20%plasma assay that is conceptually similar to the 2.5% assay. Twomicroliters of compound are added to dry, 96-well, half-area microtiterplates followed by 48 ul of 40% human plasma (diluted in PBS) and 50 ulof 40% donor solution. The fluorescent intensity is monitored after 3 hrincubation at room temperature. In the case of either the 2.5% or the20% assay, the percent inhibition of CE transfer by compound iscalculated by comparing to wells containing fluorescent donors andplasma but no compound.

CETP in Vivo Assay

Activity of these compounds in vivo can be determined by the amount ofagent required to be administered, relative to control, to inhibitcholesteryl ester transfer activity by 50% at various time points exvivo or to elevate HDL cholesterol by a given percentage in aCETP-containing animal species. Transgenic mice expressing both humanCETP and human apolipoprotein Al (Charles River, Boston, Mass.) may beused to assess compounds in vivo. The compounds to be examined areadministered by oral gavage in an emulsion vehicle containing 20% (v:v)olive oil and 80% sodium taurocholate (0.5%). Blood is taken from miceretroorbitally before dosing, if a predose blood sample is desirable. Atvarious times after dosing, ranging from 4 h to 24 h, the animals aresacrificed, blood obtained by heart puncture, and lipid parametersmeasured, including total cholesterol, HDL and LDL cholesterol, andtriglycerides. CETP activity is determined by a method similar to thatdescribed above except that ³H-cholesteryl oleate-containing LDL is usedas the donor source as opposed to HDL. The values obtained for lipidsand transfer activity are compared to those obtained prior to dosingand/or to those from mice receiving vehicle alone.

Plasma Lipids Assay

The activity of these compounds may also be demonstrated by determiningthe amount of agent required to alter plasma lipid levels, for exampleHDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levelsor triglycerides, in the plasma of certain mammals, for examplemarmosets that possess CETP activity and a plasma lipoprotein profilesimilar to that of humans (Crook et al. Arteriosclerosis 10, 625, 1990).Adult marmosets are assigned to treatment groups so that each group hasa similar mean±SD for total, HDL, and/or LDL plasma cholesterolconcentrations. After group assignment, marmosets are dosed daily withcompound as a dietary admix or by intragastric intubation for from oneto eight days. Control marmosets receive only the dosing vehicle. Plasmatotal, LDL VLDL and HDL cholesterol values can be determined at anypoint during the study by obtaining blood from an antecubital vein andseparating plasma lipoproteins into their individual subclasses bydensity gradient centrifugation, and by measuring cholesterolconcentration as previously described (Crook et al. Arteriosclerosis 10,625, 1990).

In Vivo Atherosclerosis Assay

Anti-atherosclerotic effects of the compounds can be determined by theamount of compound required to reduce the lipid deposition in rabbitaorta. Male New Zealand White rabbits are fed a diet containing 0.2%cholesterol and 10% coconut oil for 4 days (meal-fed once per day).Rabbits are bled from the marginal ear vein and total plasma cholesterolvalues are determined from these samples. The rabbits are then assignedto treatment groups so that each group has a similar mean±SD for totalplasma cholesterol concentration, HDL cholesterol concentration,triglyceride concentration and/or cholesteryl ester transfer proteinactivity. After group assignment, rabbits are dosed daily with compoundgiven as a dietary admix or on a small piece of gelatin basedconfection. Control rabbits receive only the dosing vehicle, be it thefood or the gelatin confection. The cholesterol/coconut oil diet iscontinued along with the compound administration throughout the study.Plasma cholesterol values and cholesteryl ester transfer proteinactivity can be determined at any point during the study by obtainingblood from the marginal ear vein. After 3-5 months, the rabbits aresacrificed and the aortae are removed from the thoracic arch to thebranch of the iliac arteries. The aortae are cleaned of adventitia,opened longitudinally and then analyzed unstained or stained with SudanIV as described by Holman et. al. (Lab, Invest. 1958, 7, 42-47). Thepercent of the lesioned surface area is quantitated by densitometryusing an Optimas Image Analyzing System (Image Processing Systems).Reduced lipid deposition is indicated by a reduction in the percent oflesioned surface area in the compound-receiving group in comparison withthe control rabbits.

Antiobesity Protocol

The ability of CETP inhibitors to cause weight loss can be assessed inobese human subjects with body mass index (BMI)≧30 kg/m². Doses ofinhibitor are administered sufficient to result in an increase of ≧25%in HDL cholesterol levels. BMI and body fat distribution, defined aswaist (W) to hip (H) ratio (WHR), are monitored during the course of the3-6 month studies, and the results for treatment groups compared tothose receiving placebo.

In Vivo Sepsis Assay

In vivo studies show that transgenic mice expressing human apo-AI andelevated HDL levels are protected from septic shock. Thus the ability ofCETP inhibitors to protect from septic shock can be demonstrated intransgenic mice expressing both human apo-AI and human CETP transgenes(Levine, D. M., Parker, T. S., Donnelly, T. M., Walsh, A. M. and Rubin,A. L., 1993. Proc. Natl. Acad. Sci. 90, 12040-44). LPS derived from E.coli is administered at 30 mg/kg by i.p. injection to animals which havebeen administered a CETP inhibitor at an appropriate dose to result inelevation of HDL. The number of surviving mice is determined at times upto 48 h after LPS injection and compared to those mice administeredvehicle (minus CETP inhibitor) only.

In Vivo Blood Pressure Assay

In Vivo Rabbit Model

Methods: New Zealand White male rabbits (3-4 kg) are anesthetized withsodium pentobarbital (30 mg/kg, i.v.) and a surgical plane of anesthesiais maintained by a continuous infusion of sodium pentobarbital (16mg/kg/hr) via an ear vein catheter. A tracheotomy is performed through aventral midline cervical incision and the rabbits are ventilated with100% oxygen using a positive pressure ventilator. Body temperature ismaintained at 38.5° C. using a heating pad connected to a YSItemperature controller model 72 (Yellow Springs instruments, YellowSprings, Md.). Fluid-filled catheters are placed in the right jugularvein (for intravenous drug administration) and in the right carotidartery for arterial pressure monitoring and for blood gas analysis usinga model 248 blood gas analyzer (Bayer Diagnostics, Norwood, Mass.). Theventilator is adjusted as needed to maintain blood pH and pCO₂ withinnormal physiological ranges for rabbits. Arterial pressure is measuredusing a strain gauge transducer (Spectromed, Oxnard, Calif.), previouslycalibrated using a mercury manometer, positioned at the level of theheart and connected to the arterial catheter. Arterial pressure signalsare digitized at 500 Hz and analyzed using a Po—Ne-Mah Data AcquisitionSystem (Gould Instrument Systems, Valley View, Ohio) to obtain meanarterial pressure and heart rate values. Baseline values are collectedwhen mean arterial pressure and heart rate have stabilized. The testcompound is then administered either as a subcutaneous (SC) bolus or asan intravenous (IV) infusion. For subcutaneous (SC) dosing the testcompound can be dissolved in an appropriate vehicle such as 5% ethanolin water (5% EtOH: 95% H₂O), while for intravenous dosing the testcompound can be dissolved in an appropriate vehicle such as 0.9% normalsaline. Arterial pressure and heart rate are monitored continuously for4 hours following dosing of the test compound or for the duration of acontinuous 4 hour infusion of the test compound. Blood is sampled afterdosing or during the infusion of the test compound to determine plasmaconcentrations of the test compounds.In vivo Primate ModelMethods: Adult M. fascicularis primates (6-8 kg) that have beenpreviously instrumented with subcutaneous vascular access ports in thedescending thoracic aorta and conditioned to sit quietly in speciallydesigned primate-restraining chairs are used. All primates are fastedfor 12-18 hours prior to the experiment. On the day of the experiment,with the primates restrained in the chairs, a strain gauge pressuretransducer (Spectromed, Oxnard, Calif.), previously calibrated using amercury manometer, is positioned at the level of the heart and connectedto the vascular access port to measure arterial pressure. The primatesare allowed to acclimate to the chair for at least one hour. Arterialpressure signals are digitized at 500 Hz and continuously recordedthroughout the experiment and analyzed using a Po—Ne-Mah DataAcquisition System (Gould Instrument Systems, Valley View, Ohio) toobtain the measurements of mean arterial pressure and heart rate.Baseline values are collected when the primates are sitting calmly andwhen mean arterial pressure and heart rate have stabilized. The testcompound is then administered as a subcutaneous (SC) bolus of a solutionof the test compound in an appropriate vehicle such as 5% ethanol inwater (5% EtOH: 95% H₂O). The solution of test compound or vehicle isfiltered through a 0.22 micron filter prior to injection and a typicaldosing volume is 0.2 ml/kg. Arterial pressure and heart rate aremonitored continuously for 4 hours following dosing of the test compoundand are recorded at selected time intervals for data comparison (vehiclevs test compound). Blood samples (1.5 ml) are withdrawn to determineplasma concentrations of the test compound and withdrawn blood isimmediately replaced with 0.9% sterile saline to maintain blood volume.

Administration of the compounds of this invention can be via any methodwhich delivers a compound of this invention systemically and/or locally.These methods include oral routes, parenteral, intraduodenal routes,etc. Generally, the compounds of this invention are administered orally,but parenteral administration (e.g., intravenous, intramuscular,subcutaneous or intramedullary) may be utilized, for example, where oraladministration is inappropriate for the target or where the patient isunable to ingest the drug.

In general an amount of a compound of this invention is used that issufficient to achieve the therapeutic effect desired (e.g., HDLelevation).

In general an effective dosage for the compounds of this invention isabout 0.001 to 100 mg/kg/day of the compound, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug. Anespecially preferred dosage is about 0.01 to 10 mg/kg/day of thecompound, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug.

A dosage of the combination pharmaceutical agents to be used inconjunction with the CETP inhibitors is used that is effective for theindication being treated.

For example, typically an effective dosage for HMG-CoA reductaseinhibitors is in the range of 0.01 to 100 mg/kg/day. In general aneffect dosage for a PPAR modulator is in the range of 0.01 to 100mg/kg/day.

The compounds of the present invention are generally administered in theform of a pharmaceutical composition comprising at least one of thecompounds of this invention together with a pharmaceutically acceptablevehicle, diluent or carrier as described below. Thus, the compounds ofthis invention can be administered individually or together in anyconventional oral, parenteral, rectal or transdermal dosage form.

For oral administration a pharmaceutical composition can take the formof solutions, suspensions, tablets, pills, capsules, powders, and thelike. Tablets containing various excipients such as sodium citrate,calcium carbonate and calcium phosphate are employed along with variousdisintegrants such as starch and preferably potato or tapioca starch andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. A preferred formulation is a solution or suspension in an oil,for example, a vegetable oil, such as olive oil; triglycerides such asthose marketed under the name, Miglyol™; or mono- or diglycerides suchas those marketed under the name, Capmul™, for example, in a softgelatin capsule. Antioxidants may be added to prevent long-termdegradation as appropriate. When aqueous suspensions and/or elixirs aredesired for oral administration, the compounds of this invention can becombined with various sweetening agents, flavoring agents, coloringagents, emulsifying agents and/or suspending agents, as well as suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

Pharmaceutical compositions comprising a solid amorphous dispersion of acholesteryl ester transfer protein (CETP) inhibitor and aconcentration-enhancing polymer are described in InternationalPublication Nos. WO 02/11710 and WO 03/000238, which are herebyincorporated by reference herein. Self-emulsifying formulations ofcholesteryl ester transfer protein (CETP) inhibitors are described inInternational Publication No. WO 03/000295, which is hereby incorporatedby reference herein. Methods for depositing small drug crystals onexcipients are set forth in the literature, such as in J. Pharm.Pharmacol. 1987, 39.769-773, which is hereby incorporated by referenceherein.

For purposes of parenteral administration, solutions in sesame or peanutoil or in aqueous propylene glycol can be employed, as well as sterileaqueous solutions of the corresponding water-soluble salts. Such aqueoussolutions may be suitably buffered, if necessary, and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. These aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal injection purposes. In this connection,the sterile aqueous media employed are all readily obtainable bystandard techniques well-known to those skilled in the art.

For purposes of transdermal (e.g., topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, are prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples of methodsof preparing pharmaceutical compositions, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

Pharmaceutical compositions according to the invention may contain0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In anyevent, the composition or formulation to be administered will contain aquantity of a compound(s) according to the invention in an amounteffective to treat the disease/condition of the subject being treated,e.g., atherosclerosis.

Since the present invention has an aspect that relates to the treatmentof the disease/conditions described herein with a combination of activeingredients which may be administered separately, the invention alsorelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof the present invention, a prodrug thereof or a salt of such compoundor prodrug and a second compound as described above. The kit comprisesmeans for containing the separate compositions such as a container, adivided bottle or a divided foil packet. Typically the kit comprisesdirections for the administration of the separate components. The kitform is particularly advantageous when the separate components arepreferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of compounds of the presentinvention can consist of one tablet or capsule while a daily dose of thesecond compound can consist of several tablets or capsules and viceversa. The memory aid should reflect this.

In another specific embodiment of the invention, a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

The compounds of this invention either alone or in combination with eachother or other compounds generally will be administered in a convenientformulation. The following formulation examples only are illustrativeand are not intended to limit the scope of the present invention.

In the formulations which follow, “active ingredient” means a compoundof this invention.

Formulation 1: Gelatin Capsules

Hard gelatin capsules are prepared using the following:

Ingredient Quantity (mg/capsule) Active ingredient 0.25-100   Starch, NF 0-650 Starch flowable powder 0-50 Silicone fluid 350 centistokes 0-15

A tablet formulation is prepared using the ingredients below:

Formulation 2: Tablets Ingredient Quantity (mg/tablet) Active ingredient0.25-100   Cellulose, microcrystalline 200-650  Silicon dioxide, fumed10-650 Stearate acid 5-15

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 0.25-100 mg of active ingredientsare made up as follows:

Formulation 3: Tablets Ingredient Quantity (mg/tablet) Active ingredient0.25-100 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone(as 10% solution in water) 4 Sodium carboxymethyl cellulose 4.5Magnesium stearate 0.5 Talc 1

The active ingredients, starch, and cellulose are passed through a No.45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.25-100 mg of active ingredient per 5 mldose are made as follows:

Formulation 4: Suspensions Ingredient Quantity (mg/5 ml) Activeingredient 0.25-100 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purified Waterto 5 mL

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form smoothpaste. The benzoic acid solution, flavor, and color are diluted withsome of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

An aerosol solution is prepared containing the following ingredients:

Formulation 5: Aerosol Ingredient Quantity (% by weight) Activeingredient 0.25 Ethanol 25.75 Propellant 22 70.00(Chlorodifluoromethane)

The active ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C., and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining propellant. The valve units arethen fitted to the container.

Suppositories are prepared as follows:

Formulation 6: Suppositories Ingredient Quantity (mg/suppository) Activeingredient 250 Saturated fatty acid glycerides 2,000

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

An intravenous formulation is prepared as follows:

Formulation 7: Intravenous Solution Ingredient Quantity Activeingredient dissolved in ethanol 1%   20 mg Intralipid ™ emulsion 1,000mL

The solution of the above ingredients is intravenously administered to apatient at a rate of about 1 mL per minute.

Soft gelatin capsules are prepared using the following:

Formulation 8: Soft Gelatin Capsule with Oil Formulation IngredientQuantity (mg/capsule) Active ingredient 10-500 Olive Oil or Miglyol ™Oil 500-1000

The active ingredient above may also be a combination of agents.

General Experimental Procedures

The following examples are put forth so as to provide those of ordinaryskill in the art with a disclosure and description of how the compounds,compositions, and methods claimed herein are made and evaluated, and areintended to be purely exemplary of the invention and are not intended tolimit the scope of what the inventors regard as their invention. Unlessindicated otherwise, percent is percent by weight given the componentand the total weight of the composition, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric. Commercialreagents were utilized without further purification. Room or ambienttemperature refers to 20-25° C. All non-aqueous reactions were run undera nitrogen atmosphere for convenience and to maximize yields.Concentration in vacuo means that a rotary evaporator was used. Thenames for the compounds of the invention were created by the Autonom 2.0PCbatch version from Beilstein Informationssysteme GmbH (ISBN3-89536-976-4) or by Chemdraw® Ultra, CambridgeSoft Corporation,Cambridge Mass. The chemical structures depicted may be only exemplaryof the general structure or of limited isomers, and not include specificstereochemistry as recited in the chemical name. Some of the examplesare prepared in a racemic form and a procedure for resolving theracemate into individual enantiomers is described. In certain cases theabsolute stereochemistry of these enantiomers is not determined howeverboth are within the scope of this invention. In these cases the order ofpresentation of the enantiomeric structures does not imply anyrelationship to their chromatographic order of separation.

NMR spectra were recorded on a Varian Unity 400 (Varian Co., Palo Alto,Calif.) NMR spectrometer at ambient temperature. Chemical shifts areexpressed in parts per million (δ) relative to an external standard(tetramethylsilane). The peak shapes are denoted as follows: s, singlet;d, doublet, t, triplet, q, quartet, m, multiplet with the prefix brindicating a broadened signal. The coupling constant (J) data given havea maximum error of ±0.41 Hz due to the digitization of the spectra thatare acquired. Mass spectra were obtained by (1) atmospheric pressurechemical ionization (APCI) in alternating positive and negative ion modeusing a Fisons Platform II Spectrometer or a Micromass MZD Spectrometer(Micromass, Manchester, UK) or (2) electrospray ionization inalternating positive and negative ion mode using a Micromass MZDSpectrometer (Micromass, Manchester, UK) with a Gilson LC-MS interface(Gilson Instruments, Middleton, Wis.), (3) a QP-8000 mass spectrometer(Shimadzu Corporation, Kyoto, Japan) operating in positive or negativesingle ion monitoring mode, utilizing electrospray ionization oratmospheric pressure chemical ionization or (4) a Hewlett Packard HP6890gas chromatograph (Agilent Technologies Inc., Santa Clara, Calif.)coupled to a Hewlett Packard HP5973 electron impact quadrupole massspectrometer. Where the intensity of chlorine or bromine-containing ionsare described, the expected intensity ratio was observed (approximately3:1 for ³⁵Cl/³⁷Cl-containing ions and 1:1 for ⁷⁹Br/⁸¹Br-containing ions)and the position of only the lower mass ion is given unless statedotherwise.

Column chromatography was performed with either Baker Silica Gel (40 μm)(J. T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (40-63 μm)(EMSciences, Gibbstown, N.J.). Flash chromatography was performed using aFlash 12 or Flash 40 column (Biotage, Dyar Corp., Charlottesville, Va.)or a CombiFlash Companion system using RediSep silica columns (TeledyneIsco, Teledyne Technologies Company, Lincoln, Nebr.). Radialchromatography was performed using a chromatotron Model 7924T (HarrisonResearch, Palo Alto, Calif.). Preparative HPLC purification wasperformed on a Shimadzu 10A preparative HPLC system (ShimadzuCorporation, Kyoto, Japan) using a model SIL-10A autosampler and model8A HPLC pumps.

Preparative HPLC purification was performed on a Waters FractionlynxLC/MS/UV system (Waters Corporation; Milford, Mass., USA) equipped withmodel 2767 injector/collector, model 2525 high flow binary pump modifiedby a model 515 low flow pump, a model 515 low flow pump for makeup flow,model GS splitter, model ZQ single quad mass spectrometer on the lowflow side, model 996 photodiode array UV detector on the high flow sidein pre-collector configuration, and a model 2487 dual UV detector on thehigh flow side in post-collector configuration. Fraction trigger isperformed by the ZQ detector in electrospray positive (ESI+) ionizationmode operating on single mass triggering. Chromatography methods areeither 0.05% trifluoroacetic acid or 0.10% ammonia modifiedacetonitrile-water gradients. In the case of acid modified gradientsWaters Symmetry C8 or C18 (19×50 nm; 5 um) are typically used and inbasic conditions Waters Xterra MS C8 or MS C18 (19×50 mm; 5 um).

Microwave-assisted reactions were conducted in an Emrys Optimizer fromPersonal Chemistry (Uppsala, Sweden) or a Biotage Initiator from Biotage(Uppsala, Sweden).

Optical rotations were determined using a Jasco P-1020 Polarimeter(Jasco Inc., Easton, Md.)

Dimethylformamide (“DMF”), tetrahydrofuran (“THF”), toluene anddichloromethane (“DCM”) were the anhydrous grade supplied by AldrichChemical Company (Milwaukee, Wis.). Unless otherwise specified, reagentswere used as obtained from commercial sources. The terms “concentrated”and “evaporated” refer to removal of solvent at 1-200 mm of mercurypressure on a rotary evaporator with a bath temperature of less than 45°C. The abbreviation “min” stands for “minutes” and “h” or “hr” standsfor “hours.” The abbreviation “gm” or “g” stands for grams. Theabbreviation “μl” or “μL” stands for microliters.

Preparation 1: 2-Bromo-5-trifluoromethyl)benzoic acid

To a solution of n-BuLi (26.7 mL of 2.5M solution in tetrahydrofuran(THF), 66.7 mmol) in THF (130 mL) at −78° C. was added2,2,6,6-tetramethylpiperidine (22.5 mL, 133.4 mmol). The mixture wasstirred at −78° C. for 30 minutes and then carefully lowered to −100° C.using liquid nitrogen. Neat 1-bromo-4-(trifluoromethyl)benzene (15 g,66.7 mmol) was added. The mixture was kept at −100° C. for 6 hours andpoured onto freshly crushed dry ice. The resulting mixture was stirredat room temperature for 16 hours. The residue solvent was removed byevaporation. Water (150 mL) was added and the mixture was extracted withdiethyl ether (3×50 mL). The aqueous layer was acidified usingconcentrated hydrochloric acid (HCl), extracted with methylene chloride(3×50 mL). The combined organic layers were washed with saturated sodiumchloride (NaCl) (75 ml), dried with magnesium sulfate (MgSO₄), filteredand concentrated to yield the title compound as a white solid (5.41 g).¹H NMR (400 MHz, CDCl₃) δ 7.7 (dd, J=8.4, 2.3 Hz, 1H) 7.9 (d, J=8.4 Hz,1H) 8.3 (d, J=2.0 Hz, 1H). MS (ES+) Calc: 267.93, Found: 266.7 (M−1).

Preparation 2: (2-Bromo-5-(trifluoromethyl)phenyl)methanol

To an ice-cooled solution of 2-bromo-5-(trifluoromethyl)benzoic acid(5.16 g, 19 mmol) in THF (50 mL) was added borane-tetrahydrofurancomplex (70 mL of 1M solution in THF, 70 mmol). The resulting mixturewas stirred at room temperature for 16 hours. The reaction mixture wasquenched with methanol. Solvent was removed. The residue was partitionedbetween ethyl acetate (3×40 mL) and 1M sodium bicarbonate (50 mL). Thecombined organic layers were washed with saturated NaCl (50 mL), dried(MgSO₄) and concentrated to yield the title compound as an oil (4.85 g).¹H NMR (400 MHz, CDCl₃) δ 4.8 (s, 2H) 7.5 (m, 1H) 7.7 (d, J=8.2 Hz, 1H)7.8 (d, J=1.6 Hz, 1H).

Preparation 3: 1-Bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene

To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (4.7 g, 18mmol) in methylene chloride (50 mL) at −10° C. was added carbontetrabromide (CBr₄) (7.17 g, 21.6 mmol). The resulting mixture wasstirred at −10° C. for 15 minutes. Triphenylphosphine (5.61 g, 21.4mmol) was then slowly added portionwise. This mixture was stirred atroom temperature for 16 hours. The mixture was partitioned betweensaturated ammonium chloride (NH₄Cl) (50 ml) and methylene chloride (2×50mL). The combined organic layers were washed with saturated NaCl (50mL), dried (MgSO₄) and concentrated. The residue was purified by flashchromatography (silica gel) (eluted with 3:1 hexanes-ethyl acetate) toyield the title compound as a white solid (4.01 g). ¹H NMR (400 MHz,CDCl₃) δ 4.6 (s, 2H) 7.5 (dd, J=8.3, 1.6 Hz, 1H) 7.8 (m, 2H).

Preparation 4: 2-Methyl-2H-tetrazol-5-amine

The title compound was prepared according to procedures described in J.Am. Chem. Soc. 1954, 76, 923.

Preparation 5:N-(3,5-Bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

A mixture of 3,5-bis(trifluoromethyl)benzaldehyde (4 g, 16.5 mmol),2-methyl-2H-tetrazol-5-amine (1.96 g, 19.8 mmol) and molecular sieves(5-10 Å beads) in toluene (50 mL) was heated at reflux for 4 hours,after which time the solvent was removed. Ethanol (50 mL) and sodiumborohydride (1.25 g, 33 mmol) were added. The resulting mixture wasstirred at room temperature for 30 minutes and then partitioned betweensaturated NH₄Cl (50 mL) and ethyl acetate (2×50 mL). The combinedorganic layers were washed with saturated NaCl (50 mL), dried (MgSO₄),filtered and concentrated to yield the title compound as a white solid(4.7 g). ¹H NMR (400 MHz, CDCl₃) δ 4.2 (s, 3H) 4.7 (s, 1H) 4.7 (s, 1H)5.0 (t, J=6.0 Hz, 1H) 7.8 (s, 1H) 7.9 (s, 2H). MS (ES+) Calc: 325.08,Found: 325.8 (M+1).

Preparation 6:(3,5-Bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution ofN-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (3.9 g,12 mmol) in THF (50 mL) at room temperature was added potassiumtert-butoxide (KOtBu) (13.2 ml of 1M solution, 13.2 mmol) followed by1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (4 g, 12.6 mmol). Themixture was stirred at room temperature for 16 hours. Additional KOtBuin THF (13.2 mL of 1M solution, 13.2 mmol) was added and the mixture wasstirred at room temperature for 2 hours. The reaction mixture waspartitioned between water (50 mL) and ethyl acetate (3×50 mL). Thecombined organic layers were washed with saturated NaCl (50 mL), dried(MgSO₄) and concentrated. The residue was purified by flashchromatography (silica gel) (eluted with 3:1 hexane-ethyl acetate) toyield the title compound (4.72 g). ¹H NMR (400 MHz, CDCl₃) δ 4.2 (s, 3H)4.8 (s, 2H) 4.9 (s, 2H) 7.4 (dd, J=8.2, 1.7 Hz, 1H) 7.5 (d, J=1.7 Hz,1H) 7.7 (m, 3H) 7.8 (s, 1H). MS (ES⁺) Calc: 561.02, Found: 561.7 (M+1).

Preparation 7:2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzonitrile

A solution of(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine(6 g, 10.6 mmol) in DMF (20 mL) at room temperature was deoxygenated bybubbling nitrogen gas through the solution for 10 minutes. Coppercyanide (CuCN) (1.14 g, 12.8 mmol) was added to the reaction mixture andit was heated to 170° C. for 16 hours. The reaction was cooled to roomtemperature and diluted with ethyl acetate. The organic layer was washedtwice with saturated aqueous ammonium chloride solution and then washedwith brine. It was dried over sodium sulfate and concentrated. Theresidue was purified by flash chromatography (silica gel, 320 g) (elutedover a gradient 5-25% ethyl acetate and hexane) to give 2.59 g (95%) ofthe title compound as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.2 (s, 3H)4.82 (s, 2H) 4.9 (s, 2H) 7.6 (dd, 1H) 7.7 (s, 2H) 7.8(s, 2H) 7.8 (dd,1H). MS (ES⁺) Calc: 508.1, Found: 509.2 (M+1).

Preparation 8:2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde

A solution of2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzonitrile(5.45 g, 10.7 mmol) in dichloromethane was cooled to −20° C. with anacetone/dry ice bath. To this solution 7.5 mL of a 1.5 M solution ofdiisobutylaluminium hydride (DIBAL-H) (11.25 mmol) in toluene was addeddrop wise. The reaction mixture was stirred for 4 hours while the icebath warmed to room temperature. The reaction was cooled to 0° C. in icebath and solid ice (approx. 8 g) was carefully added to the reactionmixture, which was then stirred vigorously for 12 hours while warming toroom temperature. Dichloromethane was added to the mixture. The organiclayer was dried over sodium sulfate and then concentrated to give ayellow oil. The crude product was absorbed onto silica gel (120 g) andpurified by normal phase flash chromatography (ISCO gradient 5-25% ethylacetate/hexane) to give 4.4 g (80%) of the title compound as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 4.2 (s, 3H) 4.8 (s, 2H) 5.2 (s, 2H) 7.5(s, 1H) 7.7 (s, 2H) 7.78 (m, 1H) 7.9 (dd, 1H). MS (ES⁺) Calc: 511.1,Found: 512.2 (M+1).

EXAMPLE 1(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

Step A: Preparation of(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol

To a solution of2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde(244 mg, 0.48 mmoles) in THF (3 mL) at 0° C. was addedcyclohexylmagnesium bromide (18% solution in THF, 0.6 mL, 0.57 mmoles)and the reaction was allow to warm to room temperature and stirredovernight. The reaction mixture was quenched with aqueous NH₄Cl andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified over 25+S Biotage silica column (eluted with 0-30% ethylacetate in hexane) to yield 110 mg (39%) of the title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.0 (m, 6H) 1.6 (m, 3H) 1.8 (m, 1H) 1.9 (d,J=12.4 Hz, 1H) 2.2 (s, 1H) 4.2 (s, 3H) 4.6 (d, J=7.5 Hz, 1H) 4.8 (m, 4H)7.3 (s, 1H) 7.5 (m, 2H) 7.6 (s, 2H) 7.8 (s, 1H)). MS (ES⁺) Calc: 595.2,Found: 596.4 (M+1).

Step B: Preparation of(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol(35.5 mg, 0.059 mmoles) in THF (0.3 mL) at 0° C. under nitrogen wasadded sodium hydride (4.8 mg, 0.12 mmoles, 60% dispersion in mineraloil). The reaction was stirred for 30 min., allowing it to warm to roomtemperature. The reaction mixture was then treated in a dropwise mannerwith methyl iodide (11 μL, 0.179 mmoles) at 0° C. The ice bath wasremoved after the addition and the reaction was stirred at roomtemperature overnight. Solvent was removed in vacuo. The residue waspurified using silica gel chromatography over 12+S Biotage silica column(eluted with 0-30% ethyl acetate in hexanes) to yield the title compound(30.1 mg, 83%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.1 (m,6H) 1.5 (m, 1H) 1.6 (m, 2H) 1.7 (m, 1H) 1.9 (d, J=12.9 Hz, 1H) 3.1 (s,3H) 4.1 (d, J=7.1 Hz, 1H) 4.2 (s, 3H) 4.7 (d, J=15.8 Hz, 1H) 4.7 (s, 2H)4.9 (d, J=16.2 Hz, 1H) 7.3 (s, 1H) 7.5 (d, J=7.9 Hz, 1H) 7.6 (d, J=8.3Hz, 1H) 7.7 (s, 2H) 7.8 (s, 1H). MS (ES⁺) Calc: 609.2, Found: 610.4(M+1).

EXAMPLE 2 AND 3 (R)— and(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

The enantiomers of Example 1 were prepared as follows. The racemicmixture of the alcohol from Step A of Example 1 (110 mg) was dissolvedin methanol, injected onto a Chiralpak AD column (2.1 cm×25 cm) (ChiralTech Inc. Westchester, Pa., USA) and eluted using heptane/2-propanol(90:10, 20 mL/min). Enantiomer 1 (37 mg, 97.5% ee) eluted at 7.364 min,and enantiomer 2 (18.8 mg, 85% ee) eluted at 8.948 min on a ChiralpakAD-H column. Each enantiomer was converted to the title compoundaccording to the procedure described in Step B of Example 1. MS foundfor each enantiomer: 610.4 (M+1).

EXAMPLE 4(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

Step A: Preparation of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol

To a solution of(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine(from Preparation 6, 6.08 g, 10.8 mmol) in THF at 0° C. was addedisopropylmagnesium chloride/lithium chloride (21 mL, 27 mmol) in THF.The isopropylmagnesium chloride/lithium chloride reagent was preparedaccording to the procedure described in Angew. Chem. Int. Ed. 2004, 43,3333. The mixture was stirred at 0° C. for 3.5 hours.Cyclohexanecarboxaldehyde (3.3 g, 29 mmol) was added. The mixture wasstirred at 0° C. for 3.5 hours, quenched with saturated aqueous ammoniumchloride and extracted with ethyl acetate. Combined organic layers (200mL) were washed with aqueous sodium bicarbonate, brine, dried withsodium sulfate and concentrated in vacuo. The residue was purified bychromatography over 65i Biotage silica column (eluted with 0-30% ethylacetate in heptane) to afford the title compound as a yellow oil (2.98g, 46%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.92-1.17 (m, 5H) 1.24 (d,J=15.77 Hz, 1H) 1.54-1.60 (m, 1H) 1.61-1.67 (m, J=2.07 Hz, 2H) 1.73-1.79(m, 1H) 1.93 (d, J=12.86 Hz, 1H) 2.25 (s, 1H) 4.20 (s, 3H) 4.65 (d,J=7.05 Hz, 1H) 4.70 (d, J=15.77 Hz, 1H) 4.76 (t, J=15.35 Hz, 2H) 4.86(d, J=15.77 Hz, 1H) 7.34 (s, 1H) 7.50-7.59 (m, 2H) 7.65 (s, 2H) 7.77 (s,1H). MS (ES⁺) Calc: 595.2, Found: 596.5 (M+1)

Step B: Preparation of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanone

To a solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol(5.46 g, 9.17 mmol) in methylene chloride (150 mL) at room temperaturewas added Dess-Martin periodinane (4.36 g, 10.3 mmol). The mixture wasstirred at room temperature for 2 hours, diluted with ether (50 mL) and1N sodium hydroxide (40 mL) was added. The mixture was extracted withethyl acetate (2×100 mL). Combined organic layers were washed with 1Nsodium hydroxide (2×40 mL), brine (50 mL), dried with sodium sulfate andconcentrated in vacuo. The crude was purified by chromatography over40+M Biotage silica column (eluted with 0-30% ethyl acetate in heptane)to afford the title compound as a pale yellow oil (5.2 g, 96%). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.16-1.42 (m, 5H) 1.70 (d, J=12.03 Hz, 1H) 1.80(d, J=9.54 Hz, 4H) 2.96-3.05 (m, 1H) 4.18 (s, 3H) 4.79 (s, 2H) 4.82 (s,2H) 7.53 (s, 1H) 7.57 (d, J=8.30 Hz, 1H) 7.64 (d, J=7.88 Hz, 1H) 7.66(s, 2H) 7.72 (s, 1H). MS (ES⁺) Calc: 593.2, Found: 594.5 (M+1)

Step C: Preparation of(S)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol

A mixture of [IrHCl₂(COD)]₂ (54.4 mg, 0.073 mmol) and(1R,2R)—N,N′-bis[2-(diphenylphosphino)benzyl]cyclohexane-1,2-diamine(44.8 mg, 0.067 mmol) in isopropanol was stirred at room temperature for30 minutes. A solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanonein isopropanol was added to mixture followed by potassium hydroxide(44.8 mg, 0.799 mmol) and stirred at room temperature for 18 hours.Isopropanol was removed in vacuo and the crude product was purified onBiotage 40+M silica column, eluted with 0-30% ethyl acetate in heptane,to afford 3.7 g (92%) of the title compound. ¹H NMR (400 MHz, CDCl₃) δppm 0.92-1.17 (m, 5H) 1.24 (d, J=15.77 Hz, 1H) 1.54-1.60 (m, 1H)1.61-1.67 (m, J=2.07 Hz, 2H) 1.73-1.79 (m, 1H) 1.93 (d, J=12.86 Hz, 1H)2.25 (s, 1H) 4.20 (s, 3H) 4.65 (d, J=7.05 Hz, 1H) 4.70 (d, J=15.77 Hz,1H) 4.76 (t, J=15.35 Hz, 2H) 4.86 (d, J=15.77 Hz, 1H) 7.34 (s, 1H)7.50-7.59 (m, 2H) 7.65 (s, 2H) 7.77 (s, 1H). MS (ES⁺) Calc: 595.2,Found: 596.5 (M+1). 95.9% ee determined by chiral HPLC on Chiralpak AD-H(4.6 mm×25 cm) eluted at 6.912 min using 90/10 heptane/IPO (1 mL/min).

Step D: Preparation of(S)-(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of(S)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol(1.81 g, 3.04 mmol) in THF (20 mL) at 0° C. was added sodium hydride(60% dispersion in mineral oil, 254.4 mg, 6.4 mmol). The mixture wasstirred at room temperature for 30 minutes, cooled to 0° C. and methyliodide (1.31 g, 9.2 mmol) was added. The mixture was stirred at roomtemperature for 5 hours. Water (10 mL) was added and the mixture wasextracted with ethyl acetate. Combined organic layers were washed withbrine, dried with sodium sulfate and concentrated in vacuo. The residuewas purified by chromatography over 25+M Biotage silica column (elutedwith 0-30% ethyl acetate in heptane) to afford the title compound as acolorless oil (1.77 g, 96%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.93-1.14(m,5H) 1.18 (d, J=10.79 Hz, 1H) 1.43-1.54(m, 1H) 1.59-1.65(m, J=4.56 Hz,2H) 1.68-1.74 (m, J=2.49 Hz, 1H) 1.90 (d, J=12.03 Hz, 1H) 3.06 (s, 3H)4.08 (d, J=7.05 Hz, 1H) 4.21 (s, 3H) 4.71 (d, J=15.77 Hz, 1H) 4.71 (s,2H) 4.88 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.49 (d, J=8.30 Hz, 1H) 7.55(d, J=8.30 Hz, 1H) 7.66 (s, 2H) 7.78 (s, 1H). MS (ES⁺) Calc: 609.2,Found: 610.5 (M+1). [α]_(D) ²⁰=36.49 deg (c=10.05 mg/mL, acetone)Determination of absolute configuration of(S)-(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxymethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

Step A: Preparation of(2-bromo-5-trifluoromethyl-benzyloxy)-tert-butyl-dimethyl-silane

To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (fromPreparation 2, 10 g, 39 mmol) in DMF (20 mL) was added imidazole (5.87g, 86.3 mmol) followed by t-butyldimethylsilyl chloride (7.11 g, 47.2mmol) and the reaction was stirred at room temperature for 16 hours. Themixture was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was purified by chromatography over 25+M Biotagesilica column (eluted with 0-20% ethyl acetate in heptane) (5CV), 20% (1CV) to afford a colorless oil (14 g, 97%) of the title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 0.15 (s, 6H) 0.98 (s, 9H) 4.75 (s, 2H) 7.36 (m,1H) 7.60 (d, J=8.3 Hz, 1H) 7.84 (s, 1H)). GCMS: 311 (M-57, t-bu).

Step B: Preparation of[2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trifluoromethyl-phenyl]-cyclohexyl-methanone

To a solution of(2-bromo-5-trifluoromethyl-benzyloxy)-tert-butyl-dimethyl-silane (3.69g, 10 mmol) in THF (35 mL) at room temperature was added isopropylmagnesium chloride/lithium chloride (21 mL, 1.5M, 30.5 mmol) in THF. Themixture was stirred at room temperature for 3 hours. Transmetallationwas followed by GC-MS. The reaction mixture was cooled to −78° C. andCuCN.2LiCl (10 ml, 1M, 10.0 mmol) was added and stirred for 30 minutes.Cyclohexanecarbonyl chloride (2.93 g, 20.0 mmol) in 3 ml THF was addedto reaction mixture. The reaction mixture was allowed to warm to roomtemperature and stirred at room temperature for 30 minutes. Reaction wasquenched by pouring onto saturated aqueous ammonium chloride in ammoniumhydroxide solution and extracted with ethyl acetate. Combined organiclayers (200 mL) were washed with brine, dried over sodium sulfate andconcentrated in vacuo The crude product was purified on Biotage column(40+M), eluting with ethyl acetate in heptane, starting with 0-20%(10CV), 20% (2CV) to yield the title compound (4.5 g, 41.5%) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.09 (s, 6H) 0.9 (s, 9H)1.2 (m, 4H) 1.7 (m, 4H) 2.4 (m, 2H) 3.1 (m, 1H) 4.8 (s, 2H) 7.5 (d,J=7.9 Hz, 1H) 7.7 (d, J=8.3 Hz, 1H) 8.0 (s, 1H). GCMS: Calc: 400, Found:343 (M-57, t-bu).

Step C: Preparation of(S)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trifluoromethyl-phenyl]-cyclohexyl-methanol

A mixture of [IrHCl₂(COD)]₂ (33 mg, 0.044 mmol) and(1R,2R)—N,N′-bis[2-(diphenylphosphino)benzyl]cyclohexane-1,2-diamine (29mg, 0.044 mmol) in isopropanol (37 ml) was stirred at room temperaturefor 30 minutes. A solution of[2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trifluoromethyl-phenyl]-cyclohexyl-methanone(1.6 g, 4 mmol) in isopropanol (5 ml) was added to mixture followed bypotassium hydroxide (28 mg, 0.5 mmol) and stirred for 16 hours.Isopropanol was removed in vacuo and the residue was purified bychromatography over 25+M Biotage silica column eluted with ethyl acetatein heptanes 0% (1 CV), 2-20% (10CV), 20% (2CV) to yield the titlecompound (1.4 g, 87%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm0.09 (s, 6H) 0.9 (s, 9H) 1.2 (m, 3H) 1.6 (d, J=7.4 Hz, 1H) 1.7 (m, 4H)2.0 (m, 1H) 2.2 (m, 1H) 2.4 (m, 1H) 4.5 (m, 1H) 4.7 (d, J=13.7 Hz, 1H)4.8 (d, J=13.7 Hz, 1H) 7.5 (d, J=1.2 Hz, 2H) 7.6 (s, 1H). Chiral SFC,Retention timet=1.93 min. indicates product is 95.0% ee. [α]_(D)²⁰=−12.99 deg (c=9.5 mg/mL, acetone)

Step D: Preparation of(S)-tert-butyl-[2-(cyclohexyl-methoxyl-methyl)-5-trifluoromethyl-benzyloxy]-dimethyl-silane

To a solution of(S)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trifluoromethyl-phenyl]-cyclohexyl-methanol(1.4 g, 3.5 mmol) in THF (3 mL) at 0° C. under nitrogen was added sodiumhydride (278 mg, 7.0 mmol, 60% dispersion in mineral oil). The reactionwas stirred for 30 minutes, allowing it to warm to room temperature. Thereaction mixture was then treated in a dropwise manner with methyliodide (1.5 g, 650 μL, 10.4 mmol) at 0° C. The ice bath was removedafter the addition and the reaction was stirred at room temperatureovernight. Ethyl ether was added and the reaction was washed with brine,dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by chromatography on Biotage column 25+S, eluting with ethylacetate in heptane 2-30% (10CV) and 30% (3CV) to yield the titlecompound (1.0 g, 88%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm0.08 (s, 6H) 0.9 (s, 9H) 1.2 (m, 3H) 1.6 (m, 2H) 1.7 (m, 4H) 2.0 (d,J=12.8, 1H) 2.2 (m, 1H) 3.1 (s, 3H) 4.0 (d, J=7.5, 1H) 4.0 (d J=13.7,1H) 4.7 (d, J=13.7 Hz, 1H) 7.4 (d, J=7.9 Hz, 1H) 7.5 (d, J=7.9 Hz, 1H)7.7 (s, 1H).

Step E: Preparation of(S)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-phenyl]-methanol

To a solution of(S)-tert-butyl-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyloxy]-dimethyl-silane(1.13 g, 2.4 mmol) in THF (5 ml) was added a solution oftetrabutylammonium fluoride (4.8 ml, 1 M, 4.8 mmol) at room temperatureand stirred for overnight. The reaction mixture was concentrated invacuo and purified on Biotage column 25+M, eluting with 0-30% ethylacetate in heptane (10 CV), 30% (2 CV) to yield the title compound (0.6g, 73%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.8 m (m, 2H)1.1 (m, 4H) 1.3 (m, 1H) 1.5 (m, 2H) 1.6 (m, 1H) 2.0 (d, J=12.9, 1H) 2.3(m, 1H) 3.1 (s, 3H) 4.0 (d, J=7.9, 1H) 4.7 (dd, J=13.7 & 7.5 Hz, 2H) 7.3(d, J=8.3 Hz, 1H) 7.4 (d, J=7.8 Hz, 1H) 7.7 (s, 1H).

Step F: Preparation of(S)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4-trifluoromethyl-benzene

To a solution of(S)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-phenyl]-methanol(340 mg, 1.2 mmol) in methylene chloride (10 mL) at 0° C. was addedcarbon tetrabromide (485 mg, 1.46 mmol) and stirred for 10 minutesfollowed by addition of triphenylphosphine (383 mg, 1.46 mmol). Reactionwas stirred at 0° C. for 1 hour and allowed to warm to room temperatureand stirred for 16 hours. Reaction was concentrated in vacuo andpurified on 25+S Biotage column eluting with 0-20% ethyl acetate inheptane (10 CV), 20% (2CV), to yield the title compound (270 mg, 66%) asa colorless oil. This oil solidified upon standing and was recrystalizedfrom hexane to yield crystals (mp=43-45° C.), which were submitted toX-ray crystallography to establish absolute configuration. ¹H NMR (400MHz, CDCl₃) δ ppm 1.1 (m, 4H) 1.3 (m, 2H) 1.6 (m, 3H) 1.7 (m, 1H) 2.0(d, J=12.6, 1H) 3.2 (s, 3H) 4.2 (d, J=7.9, 1H) 4.5 (d, J=10.3 Hz, 1H)4.6 (d, J=10.3 Hz, 1H) 7.4 (d, J=8.3 Hz, 1H) 7.5 (d, J=8.3 Hz, 1H) 7.6(s, 1H). [α]_(D) ²⁰=−50 deg (c=11.5 mg/mL, acetone)

Step G: Preparation of(S)-(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution ofN-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (26.7mg, 0.082 mmol) in DMF (1 ml) at 0° C. under nitrogen was added sodiumhydride (6 mg, 0.1 mmol, 60% dispersion in mineral oil). The reactionwas stirred for 30 minutes while allowing it to warm to roomtemperature. The reaction mixture was then treated with(S)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4-trifluoromethyl-benzene(25 mg, 0.068 mmol) at 0° C. The ice bath was removed after the additionand the reaction was stirred at room temperature overnight. Water wasadded and the mixture was extracted with ethyl acetate. Combined organiclayers were washed with water, brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by chromatography on12+S Biotage silica column, eluting with ethyl acetate in heptane 0-30%(10CV) and 30% (3CV) to yield the title compound (20 mg, 48%) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.07 (m, 4H) 1.2 (m, 2H)1.46 (m, 1H) 1.57 (m, 2H) 1.61(m, 1H) 1.90 (d, J=12.4, 1H) 3.06 (s, 3H)4.08 (d, J=7.1, 1H) 4.2 (s, 3H) 4.70 (d, J=15.7, 1H) 4.89 (d, J=15.7,1H) 7.35 (s, 1H) 7.50 (d, J=7.9, 1H) 7.55 (d, J=7.9, 1H) 7.65 (s, 2H)7.77 (s, 1H). [α]_(D) ²⁰=−26.6 deg (c=13 mg/mL, acetone).

EXAMPLE 5(3,5-Bis-trifluoromethyl-benzyl)-{2-[methoxy-(1-methyl-piperidin-4-yl)-methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of the aldehyde from Preparation 8 (0.230 g, 0.45 mmol) inTHF (3 mL) at −78° C. was added a THF solution1-methylpiperidine-4-magnesium chloride (0.21 g, 1.35 mmol) (Collectionof Czechoslovak Chemical Communications, 47(11), 3077-93, 1982), and thesolution was stirred for 3 hours as it warmed to room temperature. Thereaction mixture was quenched with saturated NH₄Cl and extracted withCHCl₃. The extract was dried, concentrated and purified over silica gelto afford the desired alcohol. MS (ES⁺) Calc: 610.53, Found: 611.5(M+1).

To a THF solution (1 mL) of the above alcohol (0.024 g, 0.038 mmol) wasadded NaH (0.0017 g, 0.042 mmol, 60% dispersion in mineral oil) and theresulting suspension was stirred for 30 min. A THF (1 mL) solution ofmethyl 4-toluenesulfonate (0.008 g, 0.042 mmol) was added and themixture was refluxed for 12 h. The solution was cooled to roomtemperature and was quenched with saturated NH₄Cl and extracted withCH₂Cl₂. The extract was dried, concentrated and purified to yield thetitle compound. MS (ES⁺) Calc: 624.55, Found: 625.3 (M+1). ¹H NMR (400MHz, CDCl₃) δ ppm 7.8 (s, 1H), 7.63 (s, J=38.3 Hz, 2H), 7.57 (d, J=8.3Hz, 2H), 7.50 (d, 2H), 7.38 (s, 1H), 4.90 (d, J=16.2 Hz, 1H), 4.70 (q,J=14 Hz, 4H), 4.20 (s, 3H), 4.12 (d, J=7 Hz, 1H) 3.05 (s, 3H), 2.80 (dof d, J=16 Hz, 2H), 2.2 (s, 3H), 1.92 (d, J=12 Hz. 1H), 1.77 (d of t,J=21, 12 Hz, 4H), 1.5 (m, 1H), 1.38 (m, 2H), 1.05 (m, 1H).

According to the procedure described in Example 1, and usingcorresponding Grignard and alkylating reagents, Examples 6 to 15 weremade:

MS Example MS Found # Chemical Name Structure Calc M + 1 6(3,5-Bis-trifluoromethyl- benzyl)-[2-(1-methoxy-propyl)-5-trifluoromethyl- benzyl]-(2-methyl-2H- tetrazol-5-yl)-amine

555.2 556.1 7 [2-(1-Benzyloxy-propyl)- 5-trifluoromethyl-benzyl]-(3,5-bis-trifluoromethyl- benzyl)-(2-methyl-2H- tetrazol-5-yl)-amine

631.2 632.1 8 (3,5-Bis-trifluoromethyl- benzyl)-[2-(cyclopropyl-methoxy-methyl)-5- trifluoromethyl-benzyl]-(2- methyl-2H-tetrazol-5-yl)-amine

567.2 568.3 9 (3,5-Bis-trifluoromethyl- benzyl)-[2-(methoxy-phenyl-methyl)-5- trifluoromethyl-benzyl]-(2- methyl-2H-tetrazol-5-yl)-amine

603.2 604.3 10 (3,5-Bis-trifluoromethyl- benzyl)-[2-(1-methoxy-2-phenyl-ethyl)-5- trifluoromethyl-benzyl]-(2- methyl-2H-tetrazol-5-yl)-amine

617.2 618.1 11 (3,5-Bis-trifluoromethyl- benzyl)-[2-(cyclohexyl-ethoxy-methyl)-5- trifluoromethyl-benzyl]-(2- methyl-2H-tetrazol-5-yl)-amine

623.2 624.4 12* (R)-(3,5-Bis- trifluoromethyl-benzyl)-[2-(cyclohexyl-ethoxy- methyl)-5-trifluoromethyl- benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

623.2 624.1 13** (S)-(3,5-Bis- trifluoromethyl-benzyl)-[2-(cyclohexyl-ethoxy- methyl)-5-trifluoromethyl- benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

623.2 624.1 14 (3,5-Bis-trifluoromethyl- benzyl)-[2-(cyclopropyl-ethoxy-methyl)-5- trifluoromethyl-benzyl]-(2- methyl-2H-tetrazol-5-yl)-amine

581.2 582.3 15 (3,5-Bis-trifluoromethyl- benzyl)-{2-[methoxy-(tetrahydro-pyran-4-yl)- methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H- tetrazol-5-yl)-amine

611.2 612.3

* For example 12: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.94-1.19 (m, 6H) 1.07(t, J=7.05 Hz, 3H) 1.43-1.53 (m, 1H) 1.57-1.64 (m, 2H) 1.66-1.75 (m, 1H)1.94 (d, J=12.86 Hz, 1H) 3.04-3.22 (m, 2H) 4.16 (d, J=7.47 Hz, 1H) 4.21(s, 3H) 4.71 (s, 2H) 4.72 (d, J=16.18 Hz, 1H) 4.88 (d, J=16.18 Hz, 1H)7.33 (s, 1H) 7.49-7.57 (m, 2H) 7.65 (s, 2H) 7.77 (s, 1H)

**For example 13: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.94-1.19 (m, 6H) 1.07(t, J=7.05 Hz, 3H) 1.42-1.53 (m, 1H) 1.59-1.65 (m, 2H) 1.67-1.75 (m, 1H)1.94 (d, J=12.86 Hz, 1H) 3.03-3.21 (m, 2H) 4.16 (d, J=7.05 Hz, 1H) 4.21(s, 3H) 4.71 (s, 2H) 4.72 (d, J=16.18 Hz, 1H) 4.88 (d, J=16.18 Hz, 1H)7.33 (s, 1H) 7.50-7.58 (m, 2H) 7.65 (s, 2H) 7.77 (s, 1H)

EXAMPLES 16 AND 17 (R) and (S)(3,5-Bis-trifluoromethyl-benzyl)-{2-[methoxy-(tetrahydro-pyran-4-Yl)methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine

Step A: Preparation of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-(tetrahydro-pyran-4-yl)-methanol

To a suspension of magnesium in THF was added iodine followed by4-chlorotetrahydropyran in THF at 65° C. Small amount of methylmagnesiumbromide (3 drops) was added to initiate the reaction. The mixture wasstirred at 65° C. for 1.5 hours, cooled to room temperature.2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehydein THF was treated with trimethylsilyl chloride and stirred at roomtemperature for 1 hour. The Grignard was then added to the aldehyde inTHF at 0° C. via syringe. The mixture was stirred at 0° C. for 1.5hours, quenched with saturated aqueous ammonium chloride and extractedwith ethyl acetate. Combined organic layers were washed with brine,dried over sodium sulfate, and concentrated in vacuo. The residue waspurified by chromatography over 25+S Biotage silica column (eluted with0-50% ethyl acetate in hexanes) to afford the title compound as a paleyellow foam (91.6 mg, 52%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.07 (d,J=13.28 Hz, 1H) 1.27-1.37 (m, 1H) 1.40-1.52 (m, 1H) 1.77-1.89 (m, 2H)2.51 (s, 1H) 3.19-3.34 (m, 2H) 3.86 (dd, J=11.14, 3.53 Hz, 1H) 3.99 (dd,J=11.62, 3.73 Hz, 1H) 4.18 (s, 3H) 4.68-4.83 (m, 4H) 4.88 (d, J=15.35Hz, 1H) 7.34 (s, 1H) 7.55 (s, 2H) 7.64 (s, 2H) 7.77 (s, 1H). MS (ES⁺)Calc: 597.2, Found: 598.4 (M+1).The racemic alcohol mixture was separated by chiral chromatography usingpreparative HPLC (Column: Chiralcel OJ; Dimension: 5 cm×50 cm; Mobilephase: 95/5 heptane/ethanol with 0.1% DEA, Flow rate: 120 mL/minutes).The expected preparative retention times for the two enantiomers are 26minutes (Enantiomer 1) and 36 minutes (Enantiomer 2). Enantiomer 1: MSCalc: 597.2, Found: 598.4; 100% ee. Enantiomer 2: MS Calc: 597.2, Found:598.4; 100% ee

Step B: (R) and (S)(3,5-Bis-trifluoromethyl-benzyl)-{2-[methoxy-(tetrahydro-pyran-4-yl)-methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-(tetrahydro-pyran-4-yl)-methanol(enantiomer 1 from chiral separation of the racemic alcohol (STEP A)using preparative HPLC, 29.5 mg, 0.049 mmol) in THF (0.2 mL) at 0° C.was added sodium hydride (60% dispersion in mineral oil, 12 mg, 0.3mmol). The mixture was stirred at room temperature for 30 minutes,cooled to 0° C. and methyl iodide (70 mg, 30 μL, 0.5 mmol) was added.The mixture was stirred at room temperature overnight and then purifiedby chromatography over 12+S Biotage column (eluted with 0-30% ethylacetate in hexanes) to afford the title compound as a colorless oil (22mg, 73%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.02 (d, J=12.45 Hz, 1H)1.32-1.51 (m, 2H) 1.69-1.83 (m, 2H) 3.06 (s, 3H) 3.15-3.31 (m, 2H) 3.86(dd, J=11.41, 3.53 Hz, 1H) 3.97 (dd, J=11.62, 4.15 Hz, 1H) 4.15 (d,J=7.05 Hz, 1H) 4.21 (s, 3H) 4.70 (d, J=15.77 Hz, 1H) 4.71 (d, J=5.39 Hz,2H) 4.91 (d, J=15.77 Hz, 1H) 7.36 (s, 1H) 7.51 (d, J=8.30 Hz, 1H) 7.58(d, J=9.13 Hz, 1H) 7.65 (s, 2H) 7.78 (s, 1H). MS (ES⁺) Calc: 611.2,Found: 612.5 (M+1).To a solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-(tetrahydro-pyran-4-yl)-methanol(enantiomer 2 from chiral separation of the racemic alcohol (STEP A)using preparative HPLC, 26.4 mg, 0.044 mmol) in THF (0.2 mL) at 0° C.was added sodium hydride (60% dispersion in mineral oil, 12 mg, 0.3mmol). The mixture was stirred at room temperature for 30 minutes,cooled to 0° C. and methyl iodide (70 mg, 30 μL, 0.5 mmol) was added.The mixture was stirred at room temperature overnight and then purifiedby chromatography over 12+S Biotage column (eluted with 0-30% ethylacetate in hexanes) to afford the title compound as a colorless oil(20.2 mg, 75%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.02 (d, J=12.86 Hz, 1H)1.33-1.49 (m, 2H) 1.70-1.83 (m, 2H) 3.06 (s, 3H) 3.16-3.30 (m, 2H) 3.86(dd, J=11.41, 3.53 Hz, 1H) 3.97 (dd, J=11.62, 3.73 Hz, 1H) 4.15 (d,J=7.05 Hz, 1H) 4.21 (s, 3H) 4.66-4.77 (m, 3H) 4.91 (d, J=15.77 Hz, 1H)7.36 (s, 1H) 7.51 (d, J=8.30 Hz, 1H) 7.58 (d, J=7.88 Hz, 1H) 7.65 (s,2H) 7.78 (s, 1H). MS (ES⁺) Calc: 611.2, Found: 612.5 (M+1).

EXAMPLE 18(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-cyclopentyl-1-methoxy-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

Step A: Preparation of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclopentyl-methanol

To a solution of(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine(117.4 mg, 0.21 mmol) in THF (0.5 mL) at 0° C. was added iPrMgCl/LiCl inTHF (0.35 mL, 0.7 mmol). The mixture was stirred at 0° C. for 3 hours.Cyclopentanecarboxaldehyde (41 mg, 0.42 mmol) was added. The mixture wasstirred at 0° C. for 3 hours, quenched with saturated aqueous ammoniumchloride and extracted with ethyl acetate. Combined organic layers werewashed with brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified by chromatography over 25+S Biotage silicacolumn (eluted with 0-30% ethyl acetate in hexanes) to afford the titlecompound as a colorless oil (55.5 mg, 46%). ¹H NMR (400 MHz, CDCl₃) δppm 0.97-1.10 (m, 1H) 1.33-1.42 (m, 1H) 1.43-1.70 (m, 5H) 1.76-1.86 (m,1H) 2.17-2.32 (m, 1H) 2.56 (s, 1H) 4.17-4.20 (m, 3H) 4.69-4.79 (m, 3H)4.81 (s, 1H) 4.90 (d, J=15.77 Hz, 1H) 7.34 (s, 1H) 7.52 (d, J=8.71 Hz,1H) 7.58 (d, J=8.30 Hz, 1H) 7.66 (s, 2H) 7.77 (s, 1H). MS (ES⁺) Calc:581.2, Found: 582.4 (M+1).

Step B: Preparation of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclopentyl-methanone

To a solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclopentyl-methanol(44,5 mg, 0.077 mmol) in methylene chloride (1.0 mL) at room temperaturewas added Dess-Martin periodinane reagent (35.7 mg, 0.084 mmol). Themixture was stirred at room temperature for 1.5 hours. Ether and 1Nsodium hydroxide was added. The mixture was extracted with ethylacetate. Combined organic layers were washed with brine, dried oversodium sulfate and concentrated in vacuo to yield a pale yellow oil(41.6 mg, 94%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.58-1.72 (m, 4H)1.75-1.88 (m, 4H) 3.48-3.58 (m, 1H) 4.18 (s, 3H) 4.81 (s, 2H) 4.88 (s,2H) 7.53 (s, 1H) 7.57 (d, J=8.30 Hz, 1H) 7.66 (s, 2H) 7.71 (d, 1H) 7.73(s, 1H). MS (ES⁺) Calc: 579.2, Found: 580.4 (M+1).

Step C: Preparation of1-(2-{[3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-1-cyclopentyl-ethanol

To a solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclopentyl-methanone(112.5 mg, 0.194 mmol) in THF (2 mL) at room temperature was addedcerium (III) chloride (71.8 mg, 0.29 mmol). The mixture was sonicatedfor 30 minutes and stirred at room temperature for 1 hour. The mixturewas cooled to 0° C. and methylmagnesium bromide (0.2 mL of 3M solutionin THF, 0.6 mmol) was added. The mixture was stirred at 0° C. for 1.5hours, quenched with saturated aqueous ammonium chloride and extractedwith ethyl acetate. Combined organic layers were washed with brine,dried over sodium sulfate and concentrated to afford a pale yellow oil(115.2 mg, 100%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.30-1.44 (m, 2H)1.45-1.69 (m, 6H) 1.54 (s, 3H) 2.37-2.48 (m, J=7.88, 7.88 Hz, 1H) 2.90(s, 1H) 4.16 (s, 3H) 4.83 (s, 2H) 5.08 (d, J=16.18 Hz, 1H) 5.32 (d,J=16.18 Hz, 1H) 7.39 (s, 1H) 7.41 (s, 2H) 7.71 (s, 2H) 7.76 (s, 1H). MS(ES⁺) Calc: 595.2, Found: 596.5 (M+1).

Step D: Preparation of(3,5-bis-trifluoromethyl-benzyl)-[2-(1-cyclopentyl-1-methoxy-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of1-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-1-cyclopentyl-ethanol(24.8 mg, 0.041 mmol) in THF (0.2 mL) at 0° C. was added sodium hydride(60% dispersion in mineral oil, 8 mg, 0.2 mmol). The mixture was stirredat room temperature for 30 minutes, cooled to 0° C. and methyl iodide(30 μL, 0.5 mmol) was added. The mixture was stirred at room temperatureovernight. The reaction mixture was purified by chromatography over 12+SBiotage silica column (eluted with 0-20% ethyl acetate in hexanes) toafford the title compound (17 mg, 67%). ¹H NMR (400 MHz, CDCl₃) δ ppm1.07 (t, J=8.09 Hz, 2H) 1.31-1.65 (m, 6H) 1.55 (s, 3H) 2.26-2.38 (m, 1H)3.03 (s, 3H) 4.18 (s, 3H) 4.68-4.75 (m, J=16.18 Hz, 1H) 4.84 (d, J=16.18Hz, 1H) 5.08 (d, J=17.84 Hz, 1H) 5.22 (d, J=17.43 Hz, 1H) 7.31 (d,J=8.71 Hz, 1H) 7.42-7.47 (m, 2H) 7.71 (s, 2H) 7.76 (s, 1H). MS (ES⁺)Calc: 609.2, Found: 610.5 (M+1).

EXAMPLES 19 AND 20 (R) and (S)(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-cyclopentyl-1-methoxy-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

The enantiomers of example 18 were prepared as follows. The racemicmixture of the alcohol from STEP C of example 18 was separated by chiralchromatography using preparative HPLC (Column: ChiralPak AD; Dimension:5 cm×50 cm; Mobile phase 98/2 heptane/IPA:, Flow rate: 120 mL/minutes).The expected preparative retention times for the two enantiomers are 19minutes (Enantiomer 1) and 25 minutes (Enantiomer 2). Enantiomer 1: MSCalc: 595.2, Found: 100% ee. Enantiomer 2: MS Calc: 595.2, Found: 93.7%eeEach enantiomer was converted to the title compound according to theprocedure described in STEP D of example 18.

Enantiomer 1: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.07 (t, J=8.09 Hz, 2H)1.31-1.65 (m, 6H) 1.55 (s, 3H) 2.26-2.38 (m, 1H) 3.03 (s, 3H) 4.18 (s,3H) 4.68-4.75 (m, J=16.18 Hz, 1H) 4.84 (d, J=16.18 Hz, 1H) 5.08 (d,J=17.84 Hz, 1H) 5.22 (d, J=17.43 Hz, 1H) 7.31 (d, J=8.71 Hz, 1H)7.42-7.47 (m, 2H) 7.71 (s, 2H) 7.76 (s, 1H). MS (ES⁺) Calc: 609.2,Found: 610.5 (M+1).

Enantiomer 2: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.07 (t, J=8.09 Hz, 2H)1.31-1.65 (m, 6H) 1.55 (s, 3H) 2.26-2.38 (m, 1H) 3.03 (s, 3H) 4.18 (s,3H) 4.68-4.75 (m, J=16.18 Hz, 1H) 4.84 (d, J=16.18 Hz, 1H) 5.08 (d,J=17.84 Hz, 1H) 5.22 (d, J=17.43 Hz, 1H) 7.31 (d, J=8.71 Hz, 1H)7.42-7.47 (m, 2H) 7.71 (s, 2H) 7.76 (s, 1H). MS (ES⁺) Calc: 609.2,Found: 610.5 (M+1).

EXAMPLE 21 AND 22 (R) and(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopentyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

Step A: Preparation of(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)-phenyl)-(cyclopentyl)methanol

To a solution of(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)-phenyl)-(cyclopentyl)-methanone(138 mg, 0.35 mmol) in methanol (0.5 mL) at room temperature was addedsodium borohydride (40.5 mg, 1.07 mmol). The mixture was stirred at roomtemperature overnight. Methanol was removed in vacuo. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over sodium sulfate and concentrated in vacuoto yield the title compound (126.8 mg, 91%). ¹H NMR (400 MHz, CDCl₃) δppm 0.13 (s, 3H) 0.14 (s, 3H) 0.94 (s, 9H) 1.04-1.12 (m, 1H) 1.43-1.74(m, 6H) 1.87-1.97 (m, 1H) 2.30-2.44 (m, 1H) 2.62-2.75 (m, J=1.66 Hz, 1H)4.64 (d, J=8.71 Hz, 1H) 4.77 (d, J=12.86 Hz, 1H) 4.92 (d, J=12.86 Hz,1H) 7.55 (s, 2H) 7.66 (s, 1H).

Step B: Preparation of(2-(cyclopentyl(methoxy)methyl)-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane

To a solution of(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)-phenyl)-(cyclopentyl)-methanol(126.8 mg, 0.33 mmol) in THF at 0° C. was added sodium hydride (39.2 mg,0.98 mmol). The mixture was stirred at room temperature for 30 minutes,cooled to 0° C. and methyl iodide (100 μL, 1.6 mmol) was added. Themixture was stirred at room temperature overnight. Solvent was removedand the residue was purified by chromatography over 12+S Biotage silicacolumn (eluted with 0-20% ethyl acetate in hexanes) to afford the titlecompound as a colorless oil (120 mg, 91%). ¹H NMR (400 MHz, CDCl₃) δ ppm0.13 (s, 6H) 0.96 (s, 9H) 1.11-1.21 (m, 1H) 1.30-1.40 (m, 1H) 1.44-1.70(m, 5H) 1.77-1.86 (m, 1H) 2.13-2.23 (m, 1H) 3.15 (s, 3H) 4.20 (d, J=7.88Hz, 1H) 4.77 (d, J=13.69 Hz, 1H) 4.89 (d, J=13.28 Hz, 1H) 7.46-7.55 (m,2H) 7.77 (s, 1H).

Step C: Preparation of(2-(cyclopentyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)methanol

To a solution of(2-(cyclopentyl(methoxy)methyl)-5-(trifluoromethyl)benzyloxy)(tert-butyl)-dimethylsilane(120 mg, 0.298 mmol) in THF at room temperature was added TBAF in THF(1.0M, 0.45 mL, 0.45 mmol). The mixture was stirred at room temperatureovernight. Solvent was removed and the residue was purified bychromatography over 12+S Biotage silica column (eluted with 0-20% ethylacetate in hexane) to afford the title compound as a colorless oil (70mg, 81%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.05-1.16 (m, 1H) 1.23-1.35 (m,1H) 1.38-1.69 (m, 5H) 1.81-1.91 (m, 1H) 2.19-2.33 (m, 1H) 2.92-2.99 (m,1H) 3.17 (s, 3H) 4.21 (d, J=8.71 Hz, 1H) 4.80 (s, 2H) 7.47 (d, J=7.88Hz, 1H) 7.54 (d, J=7.88 Hz, 1H) 7.69 (s, 1H).The racemic mixture was separated by chiral chromatography usingpreparative HPLC (Column: ChiralPak AD; Dimension: 5 cm×50 cm; Mobilephase: 98/2 heptane/ethanol, Flow rate: 120 mL/minutes). The expectedpreparative retention times for the two enantiomers were 15 minutes(Enantiomer 1) and 20 minutes (Enantiomer 2). Enantiomer 1: ¹H NMR (400MHz, CDCl₃) δ ppm 1.05-1.17 (m, 1H) 1.26-1.37 (m, 1H) 1.42-1.72 (m, 5H)1.83-1.92 (m, 1H) 2.23-2.33 (m, 1H) 2.38-2.47 (m, 1H) 3.18 (s, 3H) 4.20(d, J=8.30 Hz, 1H) 4.82 (d, J=3.73 Hz, 2H) 7.47 (d, J=8.30 Hz, 1H) 7.55(d, J=7.88 Hz, 1H) 7.69 (s, 1H). Enantiomer 2: ¹H NMR (400 MHz, CDCl₃) δppm 1.05-1.17 (m, 1H) 1.28-1.36 (m, 1H) 1.42-1.71 (m, 5H) 1.81-1.93 (m,1H) 2.22-2.35 (m, 1H) 2.36-2.48 (m, 1H) 3.18 (s, 3H) 4.20 (d, J=8.71 Hz,1H) 4.82 (d, J=3.73 Hz, 2H) 7.47 (d, J=8.30 Hz, 1H) 7.55 (d, J=8.30 Hz,1H) 7.69 (s, 1H).

Step D: Preparation of (R) and(S)-2-(bromomethyl)-1-(cyclopentyl(methoxy)methyl)-4-(trifluoro-methyl)benzene

To a solution of(2-(cyclopentyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)methanol(enatiomer 2 from the chiral separation of the racemate in STEP C, 23.1mg, 0.080 mmol) and carbon tetrabromide (34.5 mg, 0.10 mmol) inmethylene chloride (0.5 mL) at room temperature was added triphenylphosphine (27.3 mg, 0.10 mmol). The mixture was stirred at roomtemperature overnight. Solvent was removed and the residue was purifiedby chromatography over 12+S Biotage silica column (eluted with 0-20-30%ethyl acetate in heptane) to afford the title compound (23.1 mg, 82%).¹H NMR (400 MHz, CDCl₃) δ ppm 1.15-1.27 (m, 1H) 1.34-1.44 (m, 1H)1.44-1.72 (m, 5H) 1.78-1.87 (m, 1H) 2.16-2.26 (m, 1H) 3.21 (s, 3H) 4.32(d, J=7.88 Hz, 1H) 4.57 (d, J=10.37 Hz, 1H) 4.67 (d, J=10.37 Hz, 1H)7.49-7.59 (m, 2H) 7.61 (s, 1H).The other enantiomer of the title compound was prepared in the samemanner using enantiomer 1 from the chiral separation of the racemate inSTEP C.

Step E: Preparation of (R) and(S)-(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopentyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution ofN-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (25.7mg, 0.078 mmol) in DMF (0.1 mL) at room temperature was added sodiumhydride (6 mg, 0.2 mmol). The mixture was stirred at room temperaturefor 1 hour.2-(Bromomethyl)-1-(cyclopentyl(methoxy)methyl)-4-(trifluoromethyl)benzene(Enantiomer 1 from STEP D, 23.1 mg, 0.066 mmol) in DMF (0.2 mL) wasadded. The mixture was stirred at room temperature for 2 days. Solventwas removed in vacuo. The residue was purified by chromatography over12+S Biotage silica column (eluted with 0-25% ethyl acetate in heptane)to afford the title compound (7.5 mg, 19%). ¹H NMR (400 MHz, CDCl₃) δppm 1.04-1.16 (m, 1H) 1.22-1.33 (m, 1H) 1.38-1.50 (m, 3H) 1.51-1.63 (m,2H) 1.65-1.76 (m, 1H) 2.02-2.14 (m, 1H) 3.07 (s, 3H) 4.19 (d, J=7.88 Hz,1H) 4.20-4.23 (m, 3H) 4.72 (d, J=2.49 Hz, 2H) 4.76 (d, J=16.18 Hz, 1H)4.90 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.51-7.58 (m, 2H) 7.66 (s, 2H)7.78 (s, 1H). MS (ES⁺) Calc: 595.2, Found: 596.5 (M+1)To a solution ofN-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (27.2mg, 0.084 mmol) in DMF (0.1 mL) at room temperature was added sodiumhydride (6 mg, 0.2 mmol). The mixture was stirred at room temperaturefor 1 hour.2-(Bromomethyl)-1-(cyclopentyl(methoxy)methyl)-4-(trifluoromethyl)benzene(Enantiomer 2 from STEP D, 24.5 mg, 0.070 mmol) in DMF (0.2 mL) wasadded. The mixture was stirred at room temperature overnight. Solventwas removed in vacuo. The residue was purified by chromatography over12+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane)to afford the title compound (18.6 mg, 45%). The residue was purified bychromatography over 12+S Biotage silica column (eluted with 0-30% ethylacetate in hexanes) to afford a colorless oil (18.6 mg, 45%). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.04-1.15 (m, 1H) 1.23-1.33 (m, 1H) 1.38-1.63 (m,5H) 1.66-1.75 (m, 1H) 2.03-2.11 (m, 1H) 3.07 (s, 3H) 4.19 (d, J=7.88 Hz1H) 4.21 (s, 3H) 4.72 (d, J=2.90 Hz, 2H) 4.76 (d, J=16.18 Hz, 1H) 4.90(d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.51-7.58 (m, 2H) 7.66 (s, 2H) 7.77 (s,1H). MS (ES⁺) Calc: 595.2, Found: 596.5 (M+1).

Preparation 9: 2-(2-Bromo-5-iodo-4-methylbenzyl) isoindoline-1,3-dione

To a solution of 5-bromo-2-iodo toluene (512 mg, 1.72 mmol) intrifluoroacetic acid (5 mL) was added N-(hydroxymethy) phthalimide (305mg, 1.72 mmol). The mixture developed a pink color. The solution wasstirred at room temperature for 22 hours then concentrated sulfuric acid(1 mL) was added. The homogeneous solution was stirred for 18 hours atroom temperature. Water was added and the precipitated solid collectedby filtration and dried in a current of air (0.776 gm). This material,which by proton NMR analysis contained approximately 15% of an isomericproduct, was carried forward to the following procedure without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ7.85 (m, 2H) 7.76(m, 2H) 7.5 (s,1H) 7.38(s, 1H) 4.84(s, 2H) 2.31(s, 3H).

GC-MS calc. 455, found 455.

Preparation 10: 2-(2-Bromo-4-methyl-5-(trifluoromethyl) benzyl)isoindoline-1,3-dione

To a solution of 2-(2-bromo-5-iodo-4-methylbenzyl) isoindoline-1,3-dione(560 mg, 1.22 mmol) in N,N-dimethylformamide (10 mL) was added copperiodide (467.6 mg, 2.45 mmol) and potassium fluoride (291.1 mg, 4.91mmol). The solution was heated to 120° C. After 20 minutesmethyl-2-chloro-2,2-difluoroacetate (709.71 mg, 4.91 mmol) was added tothe orange suspension and the heating was continued for 8 hours. Afterabout 30 minutes gas evolution was observed and the solution becameyellow. After cooling the mixture was poured into water (50 mL), formingan emulsion, to which was added dichloromethane (300 mL). The mixturewas stirred for 20 minutes then filtered through a pad of Celite®,rinsing through with dichloromethane. The organic layer was washed with25 mL of 2 N HCl, dried with anhydrous sodium sulfate and concentratedunder reduced pressure to a yellow solid (510 mg). This material wasrecrystallized from hot ethanol (30 mL) then allowed to stand at roomtemperature for 72 hours. The crystals were collected by filtration andrinsed with ethanol to give a white crystalline solid (314 mg). Finalpurification was achieved by recrystallization from hot acetonitrile togive the title compound (200 mg, 40%). ¹H NMR (400 MHz, CDCl₃) δ 7.86(m, 2H) 7.74(m, 2H) 7.50 (s, 1H) 7.39(s, 1H) 4.84(s, 2H) 2.32(s, 3H).GC-MS calc. 398, found 376 (M-F)

Preparation 11: (2-Bromo-4-methyl-5-(trifluoromethyl) phenyl)methanamine

A mixture of 2-(2-bromo-5-iodo-4-methylbenzyl) isoindoline-1,3-dione(460 mg, 1.15 mmol) and hydrazine hydrate (148.1 mg, 4.62 mmol) washeated under reflux for 1 hour and the volatiles removed under reducedpressure. To the residue was added 1 M sodium hydroxide (50 mL) anddichloromethane (40 mL). The mixture was stirred for 20 minutes thenfiltered through a sintered glass funnel, rinsing with dichloromethane.The organic layer was separated, the aqueous layer extracted withdichloromethane (2×75 mL) and the combined organics dried with anhydrousmagnesium sulfate and concentrated to dryness under reduced pressure.This material was purified by flash chromatography on a 4 gm RediSepcolumn (Teledyne Isco Inc., Lincoln Nebr.) (eluted with ethyl acetate)to yield the title compound (0.189 gm, 84.6%). ¹H NMR (400 MHz, CDCl₃) δ7.62 (s, 1H) 7.48(s, 1H) 3.93 (s, 2H) 2.51(s, 3H)

Preparation 12: N-(2-Bromo-4-methyl-5-(trifluoromethyl) benzyl)(3,5-bis(trifluoromethyl) phenyl) methanamine

A mixture of (2-bromo-4-methyl-5-(trifluoromethyl) phenyl) methanamine(189 mg, 0.705 mmol) and 3,5 bistrifluoromethyl benzaldehyde (170 mg,0.705 mmol) in anhydrous toluene (10 mL) was heated under reflux for 3hours. The solvent was removed under reduced pressure and the residuewas dissolved in dichloromethane (25 mL). Sodium triacetoxyborohyride(373.5 mg, 1.76 mmol) was added and the mixture was stirred for 18 hoursat room temperature. The mixture was poured into a mixture of saturatedNaHCO₃ (50 mL) and ethyl acetate (50 mL) and stirred for 30 minutes. Thelayers were separated and the aqueous layer was extracted with ethylacetate (2×50 mL). The combined organic layer was dried with anhydroussodium sulfate, filtered and concentrated to give the title compound(98.4%). ¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 2H) 7.76(s, 1H) 7.58(s, 1H)7.41 (s, 1H) 3.92(s, 2H) 3.89(s, 2H) 2.44(s, 3H)

Preparation 13: (2-Bromo-4-methyl-5-(trifluoromethyl) benzyl)(3,5-bis(trifluoromethyl) benzyl) cyanamide

N-(2-Bromo-4-methyl-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)phenyl)methanamine(89 mg, 0.180 mmol) was dissolved in methanol (10 mL). To this solutionwas added sodium carbonate (53.9 mg, 0.396 mmol) followed by cyanogenbromide (5.0M solution in acetonitrile, 21.9 mg, 0.041 mL, 0.207 mmol).The solution stirred at room temperature for 20 hours then concentratedunder reduced pressure to dryness. The residue was partitioned betweenwater (10 mL) and ethyl acetate (50 mL). The aqueous layer was extractedwith ethyl acetate (2×20 mL), the organics were combined and dried withanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to give the title compound (97.5%). ¹H NMR (400 MHz, CDCl₃) δ7.85 (s, 1H) 7.72 (s, 2H) 7.54 (s, 1H) 7.51 (s, 1H) 4.34(s, 4H) 2.45(s,3H). LC-MS calc. 519, found 520 (M+H)

Preparation 14:N-(2-Bromo-4-methyl-5-trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine

To a solution of (2-bromo-4-methyl-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl) benzyl) cyanamide (80 mg, 0.154 mmol)in toluene (10 mL) was added triethylamine hydrochloride (63.62 mg,0.462 mmol) and sodium azide (30.05 mg, 0.462 mmol). The mixture washeated to 115° C. for 18 hours, cooled, then 0.1 N hydrogen chloride (30mL) was added to the mixture and stirred for 30 minutes. The aqueouslayer was extracted with ethyl acetate (2×30 mL) and the combinedorganic layers were dried with anhydrous sodium sulfate, filtered, andconcentrated to dryness under reduced pressure. The residue was purifiedby flash chromatography on a 12 g RediSep column (Teledyne Isco Inc.,Lincoln Nebr.) (eluted with 25-100% ethyl acetate in heptane) to yieldthe title compound (66%). ¹H NMR (400 MHz, CDCl₃) δ 7.71(s, 1H) 7.59 (s,2H) 7.43(s, 1H) 7.34(s, 1H) 4.80(s, 2H) 4.77(s, 2H) 2.37(s, 3H). LC-MScalc. 562, found 563 (M+H)

Preparation 15: N-(2-Bromo-4-methyl-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl) benzyl)-2-methyl-2H-tetrazol-5-amine

To a solution ofN-(2-bromo-4-methyl-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine(76 mg, 0.135 mmol) in anhydrous THF (5 mL) was added sodium carbonate(28 mg, 0.270 mmol) and N,N-dimethylformamide (1 mL) followed bydimethyl sulfate (34 mg. 0.270 mmol). The solution was heated to 70° C.for 18 hours then the solvent was removed under reduced pressure. Theresidue was partitioned between ethyl acetate (20 mL) and water (10 mL).The aqueous layer was extracted with ethyl acetate (3×20 mL) and thecombined organics were washed with water (3×20 mL). The combinedorganics were dried with anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give the title compound (76 mg,97.5%). ¹H NMR (400 MHz, CDCl₃) δ 7.71 (s, 1H) 7.62 (s, 2H) 7.44(s, 1H)7.40(s, 1H) 4.79(s, 2H) 4.76(s, 2H) 4.20(s, 3H) 2.39(s, 3H). LC-MS calc.576 found 577 (M+H)

EXAMPLE 23(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-4-methyl-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

Step 1: Preparation of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-methyl}-5-methyl-4-trifluoromethyl-phenyl)-cyclohexyl-methanol

To a solution ofN-(2-bromo-4-methyl-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(20 mg, 0.035 mmol) in THF (0.2 mL) at 0° C. was added iPrMgCl/LiCl(0.075 mL, 0.11 mmol). The mixture was stirred at 0° C. for 3 hours andcyclohexanecarboxaldehyde (9.3 mg, 0.083 mmol) was added. The mixturewas stirred at 0° C.-room temperature for 2 hours, quenched with aqueousammonium chloride and diluted with ethyl acetate. The organic layer wasfiltered through a short pad of sodium sulfate and concentrated invacuo. The residue was purified by chromatography over 12+S Biotagesilica column (eluted with 0-30% ethyl acetate in heptane) to afford thetitle compound (8.6 mg, 41%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.91-1.32(m, 6H) 1.52-1.60 (m, 1H) 1.61-1.67 (m, 2H) 1.77 (d, 1H) 1.95 (d,J=12.86 Hz, 1H) 2.19 (d, J=3.32 Hz, 1H) 2.45 (s, 3H) 4.19 (s, 3H) 4.61(dd, J=7.47, 2.90 Hz, 1H) 4.67 (d, J=15.77 Hz, 1H) 4.64-4.79 (m, 2H)4.82 (d, J=15.35 Hz, 1H) 7.30 (s, 1H) 7.34 (s, 1H) 7.63 (s, 2H) 7.76 (s,1H). MS (ES⁺) Calc: 609.2, Found: 610.56 (M+1)

Step 2: Preparation of(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-4-methyl-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-5-methyl-4-trifluoromethyl-phenyl)-cyclohexyl-methanol(8 mg, 0.01 mmol) in THF (0.15 mL) at 0° C. was added sodium hydride(4.2 mg, 0.11 mmol). The mixture was stirred at room temperature for 30minutes. Methyl iodide (10 μL, 0.2 mmol) was added at 0° C. The mixturewas stirred at room temperature overnight. The mixture was quenched withmethanol and purified by chromatography over 12+S Biotage silica column(eluted with 0-30% ethyl acetate in heptane) to afford the titlecompound (3.6 mg, 40%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.92-1.20 (m, 6H)1.41-1.51 (m, 1H) 1.61 (d, J=8.71 Hz, 2H) 1.67-1.74 (m, 1H) 1.93 (d,J=11.62 Hz, 1H) 2.46 (s, 3H) 3.04 (s, 3H) 4.04 (d, J=7.05 Hz, 1H) 4.21(s, 3H) 4.63-4.72 (m, 3H) 4.84 (d, J=16.18 Hz, 1H) 7.27 (s, 1H) 7.30 (s,1H) 7.63 (s, 2H) 7.77 (s, 1H). MS (ES³⁰) Calc: 623.2, Found: 624.6 (M+1)According to the procedure described in example 23 and using thecorresponding aryl bromide and aldehyde reagent, example 24 wasprepared.

MS Example MS Found # Chemical Name Structure Calc M + 1 24(3,5-Bis-trifluoromethyl- benzyl)-[2-(1-methoxy-3-pyridin-3-yl-propyl)-5- trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5- yl)-amine

532.2 533.6

Preparation 16:(2-(((3,5-Bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)(cyclohexl)methanone

To a solution of(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)(cyclohexyl)methanol(53 mg, 0.086 mmol) in dichloromethane (3 mL) was added the Dess-Martinperiodinane (47.9 mg, 0.113 mmol) and the mixture was stirred at roomtemperature for 1.5 hours. Diethyl ether (20 mL) was added to thesolution followed by 2 M NaOH (5 mL). The layers were separated, theorganic layer was dried with anhydrous sodium sulfate and concentratedunder reduced pressure to give the title compound as a yellow gum (52.2mg). ¹H NMR (400 MHz, CDCl₃) δ7.70 (s, 1H) 7.62 (s, 2H) 7.48 (s, 1H)7.36 (s, 1H) 4.76 (s, 4H) 4.18 (s, 3H) 2.47 (s, 3H) 1.80 (d, J=10.0 Hz,4H) 1.22 (m, 7H). LC-MS calc. 607.5, found 608.6 (M+H).

Preparation 17:1-(2-(((3,5-Bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)-1-cyclohexylethanol

To a solution of(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)(cyclohexyl)methanone(52 mg, 0.085 mmol) in anhydrous THF (10 mL) under nitrogen at 0° C. wasadded methylmagnesium bromide (3.0 M solution in THF, 25.6 mg, 0.114 mL,0.342 mmol). The solution was stirred at 0° C. for 30 minutes, thenwarmed to room temperature and stirred for 1.5 hours. The solution wasthen poured into a mixture of 2 N hydrochloric acid (10 mL) and ethylacetate (20 mL). The solution was stirred at room temperature for 10minutes then the layers were separated and the aqueous layer wasextracted with ethyl acetate (3×15 mL). The combined organics layer wasdried with anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The crude product was purified by flash chromatographyon a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with1-50% ethyl acetate in heptane) to yield the title compound (97.2%). ¹HNMR (400 MHz, CDCl₃) δ 7.73 (s, 1H) 7.68 (s, 2H) 7.33 (s, 1H) 7.17 (s,1H) 5.39 (d, J=16.17 Hz, 1H) 4.82 (d, J=15.76 Hz, 1H) 4.77(s, 2H)4.15(s, 3H) 2.39 (s, 3H) 1.62 (m, 6H) 1.24 (s, 3H) 1.04 (m, 5H). LC-MScalc. 623.5, found 624.6 (M+H)

EXAMPLE 25N-(2-(1-cyclohexyl-1-methoxyethyl)-4-methyl-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

To a solution of1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)-1-cyclohexylethanol(18 mg, 0.028 mmol) in THF (3 mL) was added sodium hydride (60%dispersion in mineral oil, 8 mg, 0.202 mmol) at room temperature. Afterstirring for 5 minutes methyl iodide (12.2 mg, 0.086 mmol) was added andthe solution was stirred at room temperature for 18 hours. Water (5 mL)was added and the mixture was extracted with ethyl acetate (3×20 mL).The organics were combined, dried with anhydrous sodium sulfate,filtered and concentrated to give an oil (17 mg). This material waspurified by flash chromatography on a 4 g RediSep column (Teledyne IscoInc., Lincoln Nebr.) (eluted with 10% ethyl acetate in heptane) to yieldthe title compound (11 mg, 59%). ¹H NMR (400 MHz, CDCl₃) δ7.75 (s, 1H)7.70 (s, 2H) 7.39 (s, 1H) 7.01 (s, 1H) 5.19 (d, J=17.42 Hz, 1H) 5.0 (d,J=17.42 Hz, 1H) 4.74 (q, J=16.72 Hz, J=16.18 Hz, 2H) 4.17 (s, 3H) 3.0(s, 3H) 2.42 (s, 3H) 1.99 (d, J=12.40 Hz, 1H) 1.72 (m, 2H) 1.58 (s, 3H)0.99 (m, 8H). MS calc. 637.5, found 638.5 (M+H)

EXAMPLE 264-[(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-methoxy-methyl]-piperidine-1-carboxylicacid methyl ester

Step A: Preparation of tert-butyl4-[((2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl])(hydroxy)methyl)piperidine-1-carboxylate

To a solution of(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine(115 mg, 0.21 mmol) in THF (0.5 mL) at 0° C. was added i-PrMgCl/LiCl(0.3 mL, 0.39 mmol). The mixture was stirred 0° C. for 3 hours andtert-butyl 4-formylpiperidine-1-carboxylate (70.7 mg, 0.33 mmol) in THF(0.1 mL) was added. The mixture was stirred at 0° C. to room temperaturefor 3 hours and quenched with saturated aqueous ammonium chloride. Themixture was extracted with ethyl acetate. Combined organic layers werewashed with brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified by chromatography over 25+S Biotage silicacolumn (eluted with 0-50% ethyl acetate in hexanes) to afford the titlecompound (62.2 mg, 44%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.12-1.19 (m, 1H)1.20-1.32 (m, 1H) 1.43 (s, 9H) 1.69-1.78 (m, 1H) 1.89 (dd, J=13.07, 1.87Hz, 1H) 2.46-2.67 (m, 2H) 3.99-4.15 (m, 2H) 4.18 (s, 3H) 4.66-4.73 (m,2H) 4.68-4.83 (m, 4H) 4.87 (d, J=15.77 Hz, 1H) 7.33 (s, 1H) 7.55 (s, 2H)7.64 (s, 2H) 7.77 (s, 1H). MS (ES⁺) Calc: 696.2, Found: 697.6 (M+1)

Step B: Preparation of tert-butyl4-((2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(methoxy)methyl)piperidine-1-carboxylate

To a solution of tert-butyl4-((2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(hydroxy)methyl)piperidine-1-carboxylate(62.2 mg, 0.089 mmol) in THF at 0° C. was added sodium hydride (10.7 mg,0.27 mmol). The mixture was stirred at room temperature for 30 minutes,cooled to 0° C. and methyl iodide (30 μL, 0.5 mmol) was added. Themixture was stirred at room temperature overnight. The reaction wasquenched with methanol. Solvent was removed and the residue was purifiedby chromatography over 12+S Biotage silica column (eluted with 0-30%ethyl acetate in hexanes) to afford the title compound (45.9 mg, 72%).¹H NMR (400 MHz, CDCl₃) δ ppm 1.09-1.16 (m, 1H) 1.17-1.29 (m, 2H) 1.43(s, 9H) 1.58-1.69 (m, 1H) 1.84 (d, J=13.28 Hz, 1H) 2.44-2.58 (m, 2H)3.04 (s, 3H) 4.04 (d, J=12.45 Hz, 1H) 4.11 (d, J=7.47 Hz, 1H) 4.15 (d,J=7.05 Hz, 1H) 4.20 (s, 3H) 4.68 (d, J=15.77 Hz, 1H) 4.71 (s, 2H) 4.88(d, J=16.18 Hz, 1H) 7.36 (s, 1H) 7.50 (d, J=8.30 Hz, 1H) 7.57 (d, J=7.88Hz, 1H) 7.65 (s, 2H) 7.78 (s, 1H). MS (ES⁺) Calc: 710.3, Found: 711.6(M+1)

Step C: Preparation ofN-(2-(methoxy(piperidin-4-yl)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

To a solution of tert-butyl4-((2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(methoxy)methyl)piperidine-1-carboxylate(36.3 mg, 0.051 mmol) in dioxane (0.3 mL) at room temperature was added4N HCl in dioxane (0.15 mL, 0.6 mmol). The mixture was stirred at roomtemperature for 2 hours and additional HCl (0.05 mL) was added. Themixture was stirred for 2 hours. Solvent was removed in vacuo. Ethylacetate was added and removed. Isopropyl ether was added and removed toyield a thick oil The HCl salt was dissolved in methanol and filteredthrough SCX cartridge (released with ammonia in methanol) to yield thetitle compound (23.5 mg, 75%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.07-1.15(m, 1H) 1.16-1.31 (m, 2H) 1.56-1.69 (m, 1H) 1.83-1.92 (m, J=7.05 Hz, 2H)2.37-2.52 (m, 2H) 2.98 (d, J=12.45 Hz, 1H) 3.05 (s, 3H) 3.09 (s, 1H)4.13 (d, J=7.05 Hz, 1H) 4.21 (s, 3 H) 4.69 (d, J=15.77 Hz, 1H) 4.71 (d,J=3.73 Hz, 2H) 4.90 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.50 (d, J=8.30 Hz,1H) 7.56 (d, J=9.13 Hz, 1H) 7.65 (s, 2H) 7.77 (s, 1H). MS (ES⁺) Calc:610.2, Found: 611.4 (M+1)

Step D: Preparation of4-[(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-methoxy-methyl]-piperidine-1-carboxylicacid methyl ester

To a solution ofN-(2-(methoxy(piperidin-4-ylmethyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(21.5 mg, 0.035 mmol) in methylene choride at room temperature was addedHunig's base (11 mg, 15 μL, 0.084 mmol) followed by methyl chloroformate(10 μL). The mixture was stirred at room temperature overnight. Solventwas removed in vacuo and the residue was purified by chromatography over12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes)to afford the title compound (18.6 mg, 79%). ¹H NMR (400 MHz, CDCl₃) δppm 1.11-1.18(m, 1H) 1.18-1.31 (m, 2H) 1.62-1.71 (m, 1H) 1.85(d, J=13.28Hz, 1H) 2.50-2.64 (m, 2H) 3.04(s, 3H) 3.66 (s, 3H) 3.99-4.20 (m, 2H)4.16 (d, J=7.05 Hz, 1H) 4.21 (s, 3H) 4.68 (d, J=15.77 Hz, 1H) 4.71 (s,2H) 4.88 (d, J=15.77 Hz, 1H) 7.36 (s, 1H) 7.50 (d, J=8.30 Hz, 1H) 7.58(d, J=9.13 Hz, 1H) 7.64 (s, 2H) 7.78 (s, 1H). MS (ES⁺) Calc: 668.2,Found: 669.6 (M+1)

EXAMPLE 274-[(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-methoxy-methyl]-piperidine-1-carboxylicacid amide

To a solution ofN-(2-(methoxy(piperidin-4-yl)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(19.5 mg, 0.030 mmol) in methylene chloride (0.2 mL) at room temperaturewas added Hunig's base (7 mg, 10 μL, 0.06 mmol) followed by phosgene intoluene (20%, 25 μL, 0.048 mmol). The mixture was stirred at roomtemperature for 1 hour. Aqueous ammonia (0.2 mL) was added. The mixturewas stirred at room temperature overnight. Solvent was removed in vacuo.The residue was purified by chromatography over 12+S Biotage silicacolumn (eluted with 1-7% methanol in methylene chloride) to afford thetitle compound (13 mg, 62%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.15-1.21 (m,1H) 1.23-1.37(m, 2H) 1.61-1.76(m, 3H) 1.88(d, J=12.45 Hz, 1H) 2.57-2.73(m, 2H) 3.04 (s, 3H) 3.86-3.97 (m, 2H) 4.18 (d, J=7.05 Hz, 1H) 4.21 (s,3H) 4.66-4.73 (m, 3H) 4.87 (d, J=16.18 Hz, 1H) 7.36 (s, 1H) 7.50 (d,J=7.88 Hz, 1H) 7.58 (d, J=8.30 Hz, 1H) 7.64 (s, 2H) 7.78 (s, 1H). MS(ES⁺) Calc: 653.2, Found: 654.6 (M+1)

EXAMPLE 282-{4-[(2-{[3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-methoxy-methyl]-piperidin-1-yl}-acetamide

To a solution ofN-(2-(methoxy)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(19.1 mg, 0.030 mmol) and 2-bromoacetamide (5.0 mg, 0.036 mmol) inacetonitrile (0.2 mL) at room temperature was added sodium carbonate(6.5 mg, 0.061 mmol). The slurry was stirred at 50° C. overnight.Solvent was removed in vacuo. The residue was partitioned between ethylacetate and water. The organic layer was washed with brine, dried oversodium sulfate and concentrated in vacuo. The residue was purified bychromatography over 12+S Biotage silica column (eluted with 1-7%methanol in methylene chloride) to afford a colorless oil (9.2 mg, 47%).¹H NMR (400 MHz, CDCl₃) δ ppm 1.14-1.30 (m, 1H) 1.34-1.56 (m, 4H) 1.85(d, J=14.52 Hz, 1H) 1.97-2.10 (m, 2H) 2.81-3.01 (m, 4H) 3.05-3.07 (m,3H) 4.19 (d, J=6.22 Hz, 1H) 4.20-4.23 (m, 3H) 4.69 (d, J=15.77 Hz, 1H)4.71 (s, 2H) 4.89 (d, J=15.77 Hz, 1H) 5.44 (s, 1H) 7.37 (s, 1H) 7.50 (d,J=7.88 Hz, 1H) 7.58 (d, J=9.13 Hz, 1H) 7.64 (s, 2H) 7.78 (s, 1H). MS(ES⁺) Calc: 667.2, Found: 668.6 (M+1)

EXAMPLE 291-{4-[(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-methoxy-methyl]-piperidin-1-yl}-ethanone

To a solution of N-(2-(methoxypiperidin-4-ylmethyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(20.5 mg, 0.034 mmol) in methylene chloride (0.5 mL) at room temperaturewas added pyridine (10 μL, 0.1 mmol) followed by acetyl chloride (5 μL,0.07 mmol). The mixture was stirred at room temperature overnight.Solvent was removed in vacuo. The residue was purified by chromatographyover 12+S Biotage silica column (eluted with 10-100% ethyl acetate inhexanes) to afford the title compound (14 mg, 64%). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.17-1.34 (m, 3H) 1.69-1.78 (m, 1H) 1.87 (t, J=12.65 Hz,1H) 2.04 (s, 1.5H) 2.06 (s, 1.5H) 2.27-2.41 (m, 1H) 2.82-2.93 (m, 1H)3.04 (s, 3H) 3.72 (d, J=15.77 Hz, 0.5H) 3.81 (d, J=12.45 Hz, 0.5H) 4.18(d, J=6.64 Hz, 1H) 4.21 (s, 3H) 4.54-4.65 (m, 1H) 4.65-4.73 (m, 3H) 4.87(d, J=16.60 Hz, 1H) 7.37 (s, 1H) 7.50 (d, J=7.88 Hz, 1H) 7.59 (d, J=7.88Hz, 1H) 7.64 (s, 2H) 7.78 (s, 1H). MS (ES⁺) Calc: 652.2, Found: 653.5(M+1)

EXAMPLE 304-[(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-methoxy-methyl]-piperidine-1-carboxylicacid ethyl ester

To a solution ofN-(2-(methoxy(piperidin-4-yl)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(19.4 mg, 0.032 mmol) in methylene chloride (0.5 mL) at room temperaturewas added Hunig's base (8.9 mg, 12 μL, 0.069 mmol) followed by phosgenein toluene (20%, 25 μL, 0.048 mmol). The mixture was stirred at roomtemperature for 3 hours. Ammonia in ethanol (1 mL) was added and themixture was stirred at room temperature overnight. Solvent was removedin vacuo The residue was purified by chromatography over 12+S Biotagesilica column (eluted with 0-50% ethyl acetate in hexane) to afford thetitle compound (7.4 mg, 34%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.11-1.18(m,1H) 1.20-1.31 (m, 2H) 1.24(t, J=7.05 Hz, 3H) 1.61-1.71 (m, 1H) 1.85(d,J=12.86 Hz, 1H) 2.56 (q, J=14.94 Hz, 2H) 3.04 (s, 3H) 4.05-4.19 (m, 2H)4.10 (q, J=7.05 Hz, 2H) 4.16 (d, J=7.05 Hz, 1H) 4.21 (s, 3H) 4.68 (d,J=15.77 Hz, 1H) 4.71 (s, 2H) 4.88 (d, J=15.77 Hz, 1H) 7.36 (s, 1H) 7.50(d, J=7.88 Hz, 1H) 7.58 (d, J=8.71 Hz, 1H) 7.64 (s, 2H) 7.78 (s, 1H). MS(ES⁺) Calc: 682.6, Found: 683.6 (M+1)

EXAMPLE 31(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-methoxy-cyclobutyl)-5-trifluoromethyl-benzyl]-2-methyl-2Htetrazol-5-yl)-amine

Step A: Preparation of1-(2-{[(3,5-bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclobutanol

To a solution of3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amine(114.3 mg, 0.20 mmol) in THF at 0° C. was added iPrMgCl/LiCl (0.25 mL,0.32 mmol). The mixture was stirred at 0° C. for 3 hours. Cyclobutanone(21.4 mg, 0.31 mmol) was stirred with CeCl₃ (50.1 mg, 0.20 mmol) at roomtemperature for 1 hour, cooled to 0° C. and the Grignard was added. Themixture was stirred at 0° C. for 2 hours and quenched with ammoniumchloride. The mixture was extracted with ethyl acetate. Combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by chromatography over25+S Biotage silica column (eluted with 0-30% ethyl acetate in hexane)to afford the title compound (34.6 mg, 31%). ¹H NMR (400 MHz, CDCl₃) δppm 1.62-1.75 (m, 1H) 2.08-2.21 (m, 1H) 2.34-2.45 (m, 2H) 2.56-2.68 (m,2H) 3.59 (d, J=7.05 Hz, 1H) 4.16 (s, 3H) 4.84 (s, 2H) 4.86 (s, 2H) 7.38(s, 1H) 7.42-7.51 (m, 2H) 7.76 (s, 2H) 7.78 (s, 1H). MS (ES⁺) Calc:553.2, Found: 554.4 (M+1)

Step B: Preparation of(3,5-bis-trifluoromethyl-benzyl)-[2-(1-methoxy-cyclobutyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of1-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclobutanol(17.3 mg, 0.031 mmol) in THF (0.2 mL) at 0° C. was added sodium hydride(5 mg, 0.1 mmol). The mixture was stirred at room temperature for 30minutes and methyl iodide (20 μL, 0.3 mmol) was added at 0° C. Themixture was stirred at room temperature overnight. Solvent was removedin vacuo. The residue was purified by chromatography over 12+S Biotagesilica column (eluted with 0-20% ethyl acetate in hexane) to afford thetitle compound (11.1 mg, 63%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.64-1.76(m, 1H) 1.98-2.10 (m, 1H) 2.33-2.43 (m, 2H) 2.43-2.53 (m, 2H) 2.85 (s,3H) 4.17-4.21 (m, 3H) 4.75 (s 2H) 4.86 (s, 2H) 7.41-7.46 (m, 2H) 7.50(d, J=8.30 Hz, 1H) 7.73 (s, 2H) 7.76 (s, 1H). MS (ES⁺) Calc 567.2,Found: 568.4 (M+1)According to the procedure described in example 31 and using thecorresponding ketone reagent, example 32 was prepared.

MS Example MS Found # Chemical Name Structure Calc M + 1 32(3,5-Bis-trifluoromethyl- benzyl)-[2-(dicyclopropyl- methoxy-methyl)-5-trifluoromethyl-benzyl]-(2- methyl-2H-tetrazol-5-yl)- amine

607.2 576.5 (M − OMe)

EXAMPLE 33(3,5-Bis-trifluoromethyl-benzyl)-{2-[ethoxy-(tetrahydro-pyran-4-yl)-methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol(20.4 mg, 0.034 mmo) in THF (0.15 mL) at 0° C. was added sodium hydride(60% dispersion in mineral oil, 4.1 mg, 0.10 mmol). The mixture wasstirred at room temperature for 30 minutes, recooled to 0° C. and DMF (5drops) was added followed by iodoethane (8 μL, 0.10 mmol). The mixturewas stirred at room temperature overnight. Solvent was removed in vacuo.The residue was purified by chromatography over 12+S Biotage silicacolumn (eluted with 0-30% ethyl acetate in hexanes) to afford the titlecompound (11.5 mg, 54%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.0 (m, 1H) 1.1(t, J=7.1 Hz, 3H) 1.4(m, 2H) 1.7(m, 1H) 1.8(d, J=13.3 Hz, 1H) 3.2 (m,4H) 3.9 (dd, J=11.6, 3.3 Hz, 1H) 4.0 (dd, J=11.4, 3.9 Hz, 1H) 4.2 (s,3H) 4.2 (d, J=7.1 Hz, 1H) 4.7 (d, J=13.3 Hz, 1H) 4.7 (s, 2H) 4.9 (d,J=15.8 Hz, 1H) 7.3 (s, 1H) 7.6 (m, 2H) 7.6 (s, 2H) 7.8 (s, 1H). MS (ES⁺)Calc: 625.2, Found: 626.4 (M+1)According to the procedure described in example 33 and using theappropriate secondary alcohol and alkylating reagent, examples 34-40were prepared.

MS Example MS Found # Chemical Name Structure Calc M + 1 34(3,5-Bis-trifluoromethyl- benzyl)-[2-(cyclohexyl- propoxy-methyl)-5-trifluoromethyl-benzyl]-(2- methyl-2H-tetrazol-5-yl)- amine

637.2 638.6 35 3-[(2-{[(3,5-Bis- trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)- amino]-methyl}-4- trifluoromethyl-phenyl)-cyclohexyl-methoxy]- propionitrile

648.2 649.6 36 (3,5-Bis-trifluoromethyl- benzyl)-{2-[cyclohexyl-(2-methoxy-ethoxy)-methyl]- 5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5- yl)-amine

653.2 654.6 37 [2-(Allyloxy-cyclohexyl- methyl)-5-trifluoromethyl-benzyl]-(3,5-bis- trifluoromethyl-benzyl)-(2- methyl-2H-tetrazol-5-yl)-amine

635.2 636.5 38 (3,5-Bis-trifluoromethyl-benzyl)-{2-[(4,4-dimethyl-cyclohexyl)-ethoxy- methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H- tetrazol-5-yl)-amine

651.3 652.4 39 (3,5-Bis-trifluoromethyl- benzyl)-{2-[ethoxy-(4-methyl-cyclohexyl)- methyl]-5-trifluoromethyl- benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine

637.2 638.4 40 (3,5-Bis-trifluoromethyl- benzyl)-[2-(ethoxy-o-tolyl-methyl)-5-trifluoromethyl- benzyl]-(2-methyl-2H- tetrazol-5-yl)-amine

632.3

EXAMPLE 412-(5-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amino}-tetrazol-2-yl)-ethanol

Step A: Preparation of(2-((tert-butyldimetylsilyloxy)methyl)-4-(trifluoro-methyl)phenyl)(cyclohexyl)methanol

To a solution of(2-bromo-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (1.3 g,3.5 mmol) in THF at 0° C. was added i-PrMgCl/LiCl in THF (3.5 mL, 4.5mmol). The mixture was stirred at 0° C. for 4 hours andcyclohexanecarboxaldehyde (0.61 g, 0.65 mL, 5.4 mmol) was added. Themixture was stirred at 0° C.-room temperature for 1 hour, quenched withsaturated aqueous ammonium chloride and extracted with ethyl acetate.Combined organic layers were washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified bychromatography over 25+M Biotage silica column (eluted with 0-20% ethylacetate in heptane) to afford the title compound (1.27 g, 90%). ¹H NMR(400 MHz, CDCl₁₃) δ ppm 0.13 (s, 6H) 0.94 (s, 9H) 0.96-1.38 (m, 7H)1.63-1.73 (m, 2H) 1.77-1.83 (m, 1H) 2.06(d, J=13.28 Hz, 1H) 2.28 (d,J=3.73 Hz, 1H) 4.58 (dd, J=7.68, 3.94 Hz, 1H) 4.75 (d, J=13.28 Hz, 1H)4.85 (d, J=13.28 Hz, 1H) 7.53 (s, 2H) 7.68 (s, 1H).

Step B: Preparation of(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane

To a solution of(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)-phenyl)-(cyclohexyl)-methanol(1.25 g, 3.11 mmol) in THF (5 mL) at 0° C. was added sodium hydride (385mg, 9.6 mmol). The mixture was stirred at room temperature for 1 hour,cooled to 0° C. and methyl iodide (1.0 mL, 16 mmol) was added. Themixture was stirred at room temperature overnight. Water was added andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified by chromatography over 25+S Biotage silicacolumn (eluted with 0-5% ethyl acetate in heptane) to afford the titlecompound as a colorless oil (1.14 g, 88%). ¹H NMR (400 MHz, CDCl₃) δ ppm0.12 (s, 6H) 0.94-0.96 (m, 9H) 0.98-1.29 (m, 6H) 1.54-1.59 (m, 1H)1.61-1.67 (m, 2H) 1.71-1.79 (m, 1H) 2.00 (d, J=12.03 Hz, 1H) 3.13 (s,3H) 4.08 (d, J=7.47 Hz, 1H) 4.71 (d, J=13.69 Hz, 1H) 4.85 (d, J=13.69Hz, 1H) 7.44 (d, J=8.30 Hz, 1H) 7.52 (d, J=7.88 Hz, 1H) 7.76 (s, 1H).

Step C: Preparation of(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)methanol

To a solution of(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane(1.13 g, 2.4 mmol) in THF (5 mL) at room temperature was added TBAF inTHF (1.0 M, 4.8 mL, 4.8 mmol). The mixture was stirred at roomtemperature overnight. Water was added and the mixture was extractedwith ethyl acetate. Combined organic layers were washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography over 25+M Biotage silica column (eluted with0-30% ethyl acetate in heptane) to afford the title compound (633.9 mg,88%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.91-1.27 (m, 6H) 1.63-1.70 (m, 3H)1.72-1.81 (m, 1H) 2.07 (d, J=12.86 Hz, 1H) 2.33-2.42 (m, 1H) 3.18 (s,3H) 4.10 (d, J=7.88 Hz, 1H) 4.78 (dd, J=5.81, 3.32 Hz, 2H) 7.43 (d,J=7.88 Hz, 1H) 7.55 (d, J=8.30 Hz, 1H) 7.69 (s, 1H).

Step D: Preparation of2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzaldehyde

To a solution of(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)methanol (113.1mg, 0.37 mmol) in methylene chloride (2 mL) at room temperature wasadded Dess-Martin periodinane reagent (175 mg, 0.41 mmol). The mixturewas stirred at room temperature for 1 hour. 1N NaOH was added and themixture was extracted with ethyl acetate. Combined organic layers werewashed with 1N NaOH, brine, dried over sodium sulfate and concentratedin vacuo to yield the title compound (107.2 mg, 95%). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.07-1.18 (m, 4H) 1.36 (d, J=5.81 Hz, 1H) 1.53-1.69 (m, 4H)1.71-1.76 (m, J=2.49 Hz, 1H) 1.83-1.90 (m, 1H) 3.22 (s, 3H) 4.73 (d,J=6.22 Hz, 1H) 7.66 (d, J=8.30 Hz, 1H) 7.81 (dd, J=8.30, 1.66 Hz, 1H)8.14 (s, 1H) 10.41 (s, 1H).

Step E: Preparation ofN-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)phenyl)methanamine

A mixture of2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzaldehyde (107 my,0.36 mmol) and 3,5-bistrifluoromethylbenzylamine (113.8 mg, 0.37 mmol)in ethanol was stirred at room temperature overnight. Sodium borohydride(16.5 mg, 0.44 mmol) was added and the mixture was stirred at roomtemperature overnight. Solvent was removed and the residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified by chromatography over 25+S Biotage silicacolumn (eluted with 0-15% ethyl acetate in heptane) to afford the titlecompound (150 mg, 80%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.94-1.23 (m, 6H)1.51-1.59 (m, 1H) 1.62 (d, J=7.05 Hz, 2H) 1.69-1.78 (m, 1H) 1.99 (d,J=12.45 Hz, 1H) 3.17 (s, 3H) 3.83 (d, J=12.86 Hz, 1H) 3.92 (d, J=12.86Hz, 1H) 4.00 (d, J=6.64 Hz, 2H) 4.22 (d, J=7.05 Hz, 1H) 7.50 (d, J=8.30Hz, 1H) 7.55 (d, J=7.88 Hz, 1H) 7.63 (s, 1H) 7.80 (s, 1H) 7.86 (s, 2H).MS (ES³⁰) Calc: 527.2, Found: 528.5 (M+1).

Step F: Preparation of(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)benzyl)cyanamide

To a solution ofN-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)phenyl)methanamine(150 mg, 0.28 mmol) and NaOAc.3H₂O (77.6 mg, 0.57 mmol) in methanol wasadded cyanogen bromide in acetonitrile (5.0 M, 0.1 mL, 0.5 mmol). Theslurry was stirred at room temperature overnight. The mixture was loadedonto a samplet and purified by chromatography over 25+S Biotage silicacolumn (eluted with 0-30% ethyl acetate in heptane) to afford the titlecompound (144.1 mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.91-1.19 (m,6H) 1.41-1.53 (m, 1H) 1.62 (d, J=7.88 Hz, 2H) 1.71-1.79 (m, 1H) 1.96 (d,J=12.45 Hz, 1H) 3.16 (s, 3H) 4.00 (d, J=7.47 Hz, 1H) 4.32 (d, J=14.11Hz, 1H) 4.32 (s, 2H) 4.40 (d, J=14.11 Hz, 1H) 7.50 (d, J=8.30 Hz, 1H)7.54 (s, 1H) 7.63 (d, J=8.30 Hz, 1H) 7.78 (s, 2H) 7.91 (s, 1H). MS (ES⁻)Calc: 552.2, Found: 551.5 (M−1).

Step G: Preparation ofN-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine

To solution of(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)benzyl)cyanamide(144 mg, 0.26 mmol) in toluene was added sodium azide (84.9 mg, 1.31mmol) followed by TEA-HCl (178.8 mg, 1.3 mmol). The mixture was stirredat 115° C. overnight. Water was added and the mixture was extracted withethyl acetate. Combined organic layers were washed with brine, driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby chromatography over 25+S Biotage silica column (eluted with 5-50%ethyl acetate in heptane) to afford the title compound (90.9 mg, 59%).¹H NMR (400 MHz, CDCl₃) δ ppm 0.90-1.16 (m, 5H) 1.23-1.32 (m, 1H)1.49-1.61 (m, 3H) 1.69 (s, 1H) 1.97 (d, J=12.45 Hz, 1H) 3.21 (s, 3H)4.05 (d, J=7.88 Hz, 1H) 4.74-4.93 (m, 4H) 7.31 (s, 1H) 7.41 (d, J=7.88Hz, 1H) 7.52 (d, J=7.88 Hz, 1H) 7.69 (s, 2H) 7.78 (s, 1H). MS (ES⁺)Calc: 595.2, Found: 596.5 (M+1).

Step H: Preparation ofN-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-(2-(tert-butyldimethylsilyloxy)ethyl)-2H-tetrazol-5-amine

To a mixture ofN-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine(40.4 mg, 0.068 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (25mg, 22 μL, 0.10 mmol) in 2-MeTHF/DMF was added sodium carbonate (29.1mg, 0.275 mmol). The slurry was stirred at 60° C. overnight. Thereaction was diluted and filtered. The filtrate was concentrated and theresidue was purified by chromatography over 12+S Biotage silica column(eluted with 0-20% ethyl acetate in heptane) to afford the titlecompound (39.3 mg, 77%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.08 (s, 6H) 0.80(s, 9H) 0.92-1.12 (m, 5H) 1.15-1.21 (m, 1H) 1.42-1.52 (m, 1H) 1.57-1.62(m, 2H) 1.68-1.72 (m, J=2.90 Hz, 1H) 1.89 (d, J=12.44 Hz, 1H) 3.03 (s,3H) 4.05-4.09 (m, 3H) 4.54 (t, J=5.60 Hz, 2H) 4.64-4.76 (m, 3H) 4.89 (d,J=16.17 Hz, 1H) 7.35 (s, 1H) 7.47 (d, J=7.88 Hz, 1H) 7.54 (d, J=9.12 Hz,1H) 7.65 (s, 2H) 7.75 (s, 1H). MS (ES⁺) Calc: 753.3, Found: 754.6 (M+1).

Step I: Preparation of2-(5-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amino}-tetrazol-2-yl-ethanol

ToN-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-(2-(tert-butyldimethylsilyloxy)ethyl)-2H-tetrazol-5-amine(39.3 mg, 0.052 mmol) in THF (0.3 mL) at room temperature was added TBAFin THF (1.0 M, 0.1 mL, 0.1 mmol). The mixture was stirred at roomtemperature overnight. Solvent was removed and the residue was purifiedby chromatography over 12+S Biotage silica column (eluted with 0-50%ethyl acetate in heptane) to afford a colorless oil (29.5 mg, 89%). ¹HNMR (400 MHz, CDCl₃) δ ppm 0.94-1.13 (m, 5H) 1.17 (d, J=11.20 Hz, 1H)1.43-1.53 (m, 1H) 1.60 (s, 2H) 1.67-1.74 (m, J=2.90 Hz, 1H) 1.91 (d,J=12.86 Hz, 1H) 2.35-2.42 (m, 1H) 3.06 (s, 3H) 4.08 (d, J=7.05 Hz, 1H)4.12-4.16 (m, J=5.39 Hz, 2H) 4.62 (t, J=4.98 Hz, 2H) 4.72 (s, 2H) 4.75(d, J=16.18 Hz, 1H) 4.88 (d, J=16.18 Hz, 1H) 7.36 (s, 1H) 7.49 (d,J=7.88 Hz, 1H) 7.56 (d, J=8.30 Hz, 1H) 7.67 (s, 2H) 7.78 (s, 1H). MS(ES⁺) Calc: 639.2, Found: 640.5 (M+1).

EXAMPLE 42(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-carbamicacid methyl ester

To a solution of(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amine(Example 41, STEP E, 22 mg, 0.042 mmol) in dichloromethane (1 ml) wasadded diisopropylethyl amine (8.09 mg, 0.063 mmol) followed by methylchloroformate (3.94 mg, 0.042 mmol) at room temperature and stirred forovernight. Reaction mixture was then concentrated in vacuo and theproduct was purified on Biotage column (12+S), eluting with 2% ethylacetate in heptane (1 CV), 2-20% (10CV), 20% (2CV) to yield the titlecompound (7 mg, 30%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.0(m, 6H) 1.4(m, 1H) 1.5(m, 2H) 1.7(s, 1H) 1.9 (d, J=11.2 Hz, 1H) 3.0 (s,3H) 3.8(s, 3H) 4.0 (d, J=17.9 Hz, 1H) 4.6 (m, 4H) 7.25 (d, J=10.4 Hz,1H) 7.45 (d, J=7.5 Hz, 1H) 7.53 (m, 3H) 7.7 (s, 1H) 7.8 (s, 1H). MS(ES⁺) Calc: 585.2, Found: 630.3 (M+45).

EXAMPLE 43N-(3,5-Bis-trifluoromethyl-benzyl)-N-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-acetamide

To a solution(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amine(Example 41, STEP E, 20 mg, 0.038 mmol) in dichloromethane (1 ml) wasadded pyridine (9.0 mg, 0.114 mmol) followed by acetyl chloride (2.98mg, 0.038 mmol) at room temperature and stirred for overnight. Reactionmixture was diluted with dichloromethane and washed with water. Theorganic layer was dried over anhydrous magnesium sulphate andconcentrated in vacuo. The product was purified on Biotage column(12+S), eluting with 2% ethyl acetate in heptane (1 CV), 2-20% (10CV),20% (2CV) to yield the title compound (8 mg, 37%) as colorless oil. ¹HNMR (400 MHz, CDCl₃) δ ppm 0.9 (m, 6H) 1.2 (m, 3H) 1.7 (m, 1H) 1.9 (m,1H) 2.2 (s, 3H) 3.1 (s, 3H) 3.9 (m, 1H) 4.6 (m, 4H) 7.4 (m, 1H) 7.5 (m,2H) 7.6 (m, 2H) 7.8 (s, 1H). MS (ES⁺) Calc: 569.2, Found: 614.2 (M+45).

EXAMPLE 441-(3,5-Bis-trifluoromethyl-benzyl)-1-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-urea

To a solution of(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amine(Example 41, STEP E, 20 mg, 0.038 mmol) in dichloromethane (1 ml) wasadded diisopropylethyl amine (6 mg, 0.045 mmol) followed by phosgene(18.8 mg, 0.038 mmol) at room temperature and stirred for 1 hour.Reaction mixture was then treated with concentrated ammonium hydroxide(0.5 ml) and stirred at room temperature for overnight. The reactionmixture was diluted with dichloromethane, washed with water, dried overanhydrous magnesium sulphate and concentrated in vacuo. The product waspurified on Biotage column (12+S), eluting with 2% ethyl acetate inheptane (1CV), 2-20% (10CV), 20% (2CV) to yield the title compound (7mg, 30%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.0 (m, 6H) 1.4(m, 1H) 1.59 (m, 4H) 1.67 (s, 1H) 1.94 (d, J=12.4 Hz, 1H) 3.1 (s, 3H)3.92 (d, J=7.8 Hz, 1H) 4.6 (m, 4H) 7.36 (s, 1H) 7.45 (d, J=7.9 Hz, 1H)7.53 (d, J=8.3 Hz, 1H) 7.68 (s, 2H) 7.78 (s, 1H). MS (ES⁺) Calc: 570.2,Found: 615.6 (M+45).

Preparation 18: (3-Bromo-5-(trifluoromethyl)phenyl)methanol

Step A: 3-Amino-5-(trifluoromethyl)benzoic acid

To a solution of 3-nitro-5-(trifluoromethyl)benzoic acid (9.8 gm, 41.7mmol) in methanol (100 mL) was added 10% palladium on carbon (50% watercontent, 1.5 gm) and the suspension was shaken in a Parr® hydrogenationapparatus (Parr Instrument Company, Moline, Ill.) under a hydrogenatmosphere (40 psi). After 2 hours the catalyst was removed byfiltration through a pad of celite, the pad rinsed through with methanoland the solvent evaporated under reduced pressure to give the titlecompound as a yellow solid (7.90 gm, 92%).

LC-MS (ES−) Calc: 205, Found: 204 (M−H). ¹H NMR (CD₃OD) δ ppm 7.51 (brs,1H), 7.47 (brs, 1H), 7.10 (brs, 1H).

Step B: 3-Bromo-5-(trifluoromethyl)benzoic acid

To a stirred suspension of 3-amino-5-(trifluoromethyl)benzoic acid (7.90gm, 38.5 mmol) in a mixture of hydrobromic acid (43% w/v, 100 mL) andwater (100 mL) at 0° C. was slowly added a solution of sodium nitrite(7.97 gm, 0.116 mol) in water (50 mL). After 1 hour the inhomogeneousyellow liquid was added to a solution of copper (II) bromide (16.44 gm,0.115 mol) in water (100 mL) and the mixture was stirred at roomtemperature for 16 hours. The mixture was extracted with diethyl ether(250 mL), the aqueous layer was separated and extracted with diethylether (3×75 mL). The combined organic layers were dried with anhydroussodium sulfate and the solvent removed under vacuum to give the titlecompound as a yellow solid (9.0 gm, 87%) which was used in the followingreaction without further purification.

LC-MS (ES−) Calc: 269, Found: 268 (M−H). ¹H NMR (CD₃OD) δ ppm 8.38 (brs,1H), 8.23 (brs, 1H), 8.09 (brs, 1H).

Step C: (3-Bromo-5-(trifluoromethyl)phenyl)methanol

To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (2.13 gm, 7.92mmol) in anhydrous THF under nitrogen was added borane dimethylsulfidecomplex (15.83 mmol, 7.91 mL) and the mixture was stirred at roomtemperature for 16 hours. A further aliquot of borane dimethylsulfidecomplex (15.83 mmol, 7.91 mL) was then added and stirring was continuedat room temperature for a further 4 hours. LC-MS indicated completeconsumption of starting material. Methanol was added cautiously untileffervescence ceased then 2N hydrochloric acid (20 mL) was added. Themixture was stirred at room temperature for 20 hours then concentratedto dryness under reduced pressure. The residue was extracted withdiethyl ether and the solution washed with water. The organic layer wasdried with anhydrous sodium sulfate and the solvent removed undervacuum. The residue was dissolved in a mixture of dichloromethane andmethanol, silica gel was added and the solvent removed under vacuum. Thesolid was placed on a column of silica gel (50 gm) and eluted withhexane-ethyl acetate (85:15) to give the title compound as a yellow oilwhich crystallized on standing (1.16 gm, 57%).

LC-MS (ES−) Calc: 255, Found: 254 (M−H). ¹H NMR (CDCl₃) δ ppm 7.72 (brs,1H), 7.69 (brs, 1H), 7.57 (brs, 1H), 4.77 (s, 2H), 1.86 (brs, 1H).

EXAMPLE 453-{[[2-(Cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2methyl-2H-tetrazol-5-yl)amino]-methyl}-5-trifluoromethyl-benzonitrile

Step A: Preparation of 3-hydroxymethyl-5-trifluoromethyl-benzonitrile

A mixture of (3-bromo-5-trifluoromethyl-phenyl)-methanol (500 mg, 1.96mmol), zinc cyanide (230 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium (68 mg, 0.059 mmol) in DMF (2 ml) was heated by microwave at160° C. for 20 minutes. The mixture was partitioned between ethyl ether(20 ml) and water (10 ml). The aqueous layer was extracted with etherand combined organic layers were washed with brine, dried (MgSO₄) andconcentrated in vacuo. The product was purified on Biotage column(12+M), eluting with 2% ethyl acetate in heptane (1 CV), 2-20% (10 CV),20% (2CV) to yield the title compound (240 mg, 61%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ ppm 2.05 (s, 1H) 4.8 (s, 2H) 7.82 (s, 1H) 7.86(s, 2H).

Step B: Preparation of 3-bromomethyl-5-trifluoromethyl-benzonitrile

A solution of 3-hydroxymethyl-5-trifluoromethyl-benzonitrile (100 mg,0.497 mmol) in dichloromethane (1 ml) at 0° C. was treated in a dropwisemanner with a solution of phosphorus tribromide (0.3 ml, 1M, 0.3 mmol)in dichloromethane at 0° C. for 1 hour. The ice bath was removed and thereaction was stirred at room temperature for 2 hours. Reaction wasquenched with sat'd NaHCO₃ solution until reaction was no longeryellow-orange in color. Reaction was extracted with dichloromethane andorganic layer was dried over anhydrous magnesium sulphate andconcentrated in vacuo. The crude residue was purified by chromatographyon Biotage column (12+M), eluting with ethyl acetate in heptane 0-30%(10CV), 30% (2CV) to yield the title compound (56 mg, 43%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.46 (s, 2H) 7.80 (s, 1H)7.84 (s, 2H).

Step C: Preparation of 3-azidomethyl-5-trifluoromethyl-benzonitrile

A solution of 3-hydroxymethyl-5-trifluoromethyl-benzonitrile (200 mg,0.994 mmol) in toluene (1 ml) at 0° C. was treated with diphenylphosphoryl azide (328 mg, 1.19 mmol), followed by DBU (182 mg, 1.19mmol) and stirred at 0° C. for 2 hours. The ice bath was removed and thereaction was stirred at room temperature for overnight. Reaction wasdiluted with ethyl acetate and washed with 10% HCl solution, dried overanhydrous magnesium sulphate and concentrated in vacuo. The residue waspurified by silica gel chromatography over 12+S Biotage silica column(eluted with 0-30% ethyl acetate in hexanes) to yield the title compound(150 mg, 67%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.54 (s,2H) 7.82 (s, 2H) 7.88 (s, 1H).

Step D: Preparation of 3-aminomethyl-5-trifluoromethyl-benzonitrile

A solution of 3-azidomethyl-5-trifluoromethyl-benzonitrile (140 mg,0.619 mmol) in THF (1 ml) was treated with trimethyl phosphine (94.2 mg,1.24 mmol) at room temperature and stirred for 2 hours. Reaction wasquenched with water and stirred for 30 minutes. Reaction was extractedwith ethyl ether and organic layer was dried over anhydrous magnesiumsulphate and concentrated in vacuo. The crude product (70 mg, 56%) wasused without further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.64(s, 2H) 3.98 (s, 2H) 7.74 (s, 1H) 7.83 (s, 2H).

Step E: Preparation of[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

A solution of2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzaldehyde (90 mg,0.30 mmol) and 2-methyl-2H-tetrazol-5-amine (35.6 mg, 0.36 mol) intoluene (1.5 ml) was heated at 50° C. for overnight. Solvent was removedin vacuo and reaction mixture was diluted with ethanol (2 ml) andtreated with sodium borohydride (21.8 mg, 0.577 mmol) and stirred atroom temperature for overnight. Reaction mixture was concentrated invacuo and diluted with ethyl acetate (100 ml) and washed with water (30ml). Organic layer was dried over anhydrous magnesium sulphate andconcentrated in vacuo. The crude product was purified on Biotage column(12+M), eluting with 7% ethyl acetate in heptane (1 CV), 7-60% (10CV),60% (2CV) to yield the title compound (65 mg, 58%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ ppm 1.1 (m, 4H) 1.25 (s, 2H) 1.62 (m, 3H) 1.76(m, 1H) 1.99 (d, J=14.1 Hz, 1H) 3.16 (s, 3H) 4.13 (s, 3H) 4.2 (d, J=7.5Hz, 1H) 4.48 (dd, J=5.4 Hz, 1H) 4.65 (dd, J=6.6 Hz, 1H) 4.93 (m, 1H)7.47 (d, J=7.8 Hz, 1H) 7.54 (d, J=8.3 Hz, 1H) 7.67 (s, 1H). MS (ES⁺)Calc: 383.4, Found: 349.3 (M−34).

Step F: Preparation of3-{[[(2-Cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrile

To a solution of[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine(28 mg, 0.073 mmol) in DMF (2 mL) at 0° C. under nitrogen was addedsodium hydride (4.4 mg, 0.11 mmol, 60% dispersion in mineral oil). Thereaction was stirred for 30 minutes, allowing it to warm to roomtemperature. The reaction mixture was then treated with3-(bromomethyl)-5-(trifluoromethyl)benzonitrile (19.3 mg, 0.073 mmol) atroom temperature and stirred for overnight. Solvent was removed invacuo. The residue was diluted with ethyl acetate and washed with satd.sodium bicarbonate solution, water and brine, dried over anhydrousmagnesium sulphate and concentrated in vacuo. The product was purifiedon Biotage column (12+S), eluting with 2% ethyl acetate in heptane(1CV), 2-20% (10CV), 20% (2CV) to yield the title compound (21 mg, 49%)as a colorless oil, ¹H NMR (400 MHz, CDCl₃) δ ppm 1.07 (m, 4H) 1.2 (m,3H) 1.65(m, 3H) 1.73 (m, 1H) 3.18 (s, 3H) 4.06 (s, 3H) 4.2 (m, 1H)4.67-5.04 (m, 2H) 5.4 (m, 1H) 7.39 (s, 1H) 7.50 (m, 3H) 7.5 (m, 2H). MS(ES⁺) Calc: 566.2, Found: 567.5 (M+1).According to the procedures described in Examples 42-45 and using theappropriate amine, Examples 46-50 were prepared.

MS Example MS Found # Chemical Name Structure Calc M + 1 46N-(3-Cyano-5- trifluoromethyl-benzyl)-N- [2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl- benzyl]-acetamide

526.2 571.6 (M + 45) 47 N-[2-(Cyclohexyl- methoxy-methyl)-5-trifluoromethyl-benzyl]-N- (3,5-dichloro-benzyl)- acetamide

501.1 470.3 (M − 31) 48 [2-(Cyclohexyl-methoxy-methyl)-5-trifluoromethyl- benzyl]-(3,5-dichloro- benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine

541.2 542.5 49 [2-(Cyclohexyl-methoxy- methyl)-5-trifluormethyl-benzyl]-(3,5-dichloro- benzyl)-carbamic acid methyl ester

517.2 486.4 (M − 31) 50 (3-Cyano-5- trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy- methyl)-5-trifluoromethyl- benzyl]-carbamic acidmethyl ester

542.2 587.6 (M + 45)

Preparation 19: (2-bromo-5-(trifluoromethyl)benzyloxy)triisopropylsilane

To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (10 g; 39mmol) in N,N-dimethylformamide (100 mL) was added imidazole (6.82 g;100.1 mmol) and triisopropylsilyl chloride (9.6 mL; 55.2 mmol) under N₂.The reaction was stirred at room temperature for 48 hours. The reactionwas diluted with ethyl acetate and washed with water (4×) and brine. Theorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by 80 g RediSep column(Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-10% ethyl acetate inheptane) to yield the title compound (16.47 g, 100%) as a colorless oil.MS (GC) Calc: 410.0, Found: 391 (M−F). ¹H NMR (400 MHz, CDCl₃) δ ppm7.94 (s, 1H), 7.62 (d, J=8.30 Hz, 1H), 7.39 (d, J=8.30 Hz, 1H), 4.84 (s,2H), 1.25 (m, 3H), 1.12(d, 18H).

Preparation 20:1-(4-(trifluoromethyl)-2-(triisopropylsilyloxy)methyl)phenyl)cycloheptanol

To a solution of(2-bromo-5-(trifluoromethyl)benzyloxy)triisopropylsilane (604 mg; 1.47mmol) in tetrahydrofuran (4 mL) under N₂ at −78° C. was addedn-butyllithium (0.9 mL; 2.25 mmol; 2.5M in hexanes) dropwise over 10minutes. Reaction was stirred for 5 minutes. A solution ofcycloheptanone (0.21 mL; 1.78 mmol) in hexanes (1.0 mL) was addeddropwise over 6 minutes. After stirring for 1 hour at −78° C., the bathwas removed and stirred for 1 hour. The reaction mixture was quenchedwith aqueous saturated ammonium chloride and extracted with ethylacetate. The organic layer was washed twice with water and then withbrine. The organic layer was dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified over a 12 g RediSepcolumn (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-10% ethylacetate in heptane) to yield 387 mg (59.3%) of the title compound as acolorless oil. MS GC (El): Calc: 444.6, Found: 426 (M−H₂O). ¹H NMR (400MHz, CDCl₃) δ ppm 7.62 (s, 1H), 7.49 (dd, J=8.30, 7.88 Hz, 1H), 7.44 (d,J=8.30 Hz, 1H), 5.11 (s, 2H), 4.03 (s, 1H), 2.07-1.98 (m, 4H), 1.94-1.82(m, 2H), 1.79-1.69 (m, 2H), 1.67-1.5 (m, 4H), 1.19 (m, 3H), 1.08 (s,18H).

Preparation 21:(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyloxy)triisopropylsilane

To a solution of1-(4-(trifluoromethyl)-2-((triisopropylsilyloxy)methyl)phenyl)cycloheptanol(284 mg; 0.639 mmol) in tetrahydrofuran (3.5 mL) at room temperature wasadded sodium hydride (40 mg; 1 mmol; 60% dispersion in mineral oil).After stirring at room temperature for 15 minutes methyl iodide (80 uL;1.28 mmol) was added. Reaction stirred for 16 hours. More sodium hydride(20 mg; 0.5 mmol; 60% dispersion in mineral oil) was added. After 5minutes methyl iodide (0.1 mL; 1.6 mmol) was added. The reaction wasstirred for 16 hours. The reaction was quenched with water and extractedwith ethyl acetate. The organic layer was washed with water (2×) andbrine. The organic layer was dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified over a 12 g RediSepcolumn (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-15% ethylacetate in heptanes) to yield 279 mg (95.2%) of the title compound as acolorless oil. MS-GC (El): Calc: 458.6 Found: 439 (M−F). ¹H NMR (400MHz, CDCl₃) δ ppm 8.22 (d, J=1.24 Hz, 1H), 7.44 (dd, J=8.30, 1.24 Hz,1H), 7.34 (d, J=8.30 Hz, 1H), 5.11 (s, 2H), 2.95 (s, 3H), 2.16 (m, 2H),2.01 (m, 2H), 2.0 (dd, J=14.94, 14.52 Hz, 1H), 1.97 (dd, J=14.94, 14.52Hz, 1H), 1.83-1.58 (m, 6H), 1.3-1.16 (m, 2H), 1.13 (s, 12H), 1.11 (s,6H).

Preparation 22:(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)phenyl)methanol

To a solution of(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyloxy)triisopropylsilane(276 mg; 0.602 mmol) in tetrahydrofuran (3.5 mL) was addedtetrabutylammonium fluoride (0.62 mL; 0.62 mmol; 1.0 M solution intetrahydrofuran). Reaction was stirred at room temperature for 1.5hours. Solvent was evaporated under reduced pressure. The residue waspurified by 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.)(eluted with 10-30% ethyl acetate in heptane) to yield 169 mg (92.9%) ofthe title compound as a colorless gum. MS-GC (El): Calc: 302.3, Found:302 (M). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.89 (s, 1H), 7.49 (dd, J=8.30Hz, 1H), 7.40 (d, J=8.30 Hz, 1H), 5.03 (s, 2H), 3.00 (s, 3H), 2.54 (bs,1H), 2.23 (m, 2H), 2.04 (m, 2H), 1.88-1.55 (m, 8H).

Preparation 23 2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzaldehyde

To a solution of(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)phenyl)methanol (167 mg;0.552 mmol) in methylene chloride (3.0 mL) was added Dess-Martin reagent(290 mg; 0.683 mmol). Reaction was stirred at room temperature for 5hours. The reaction was diluted with ethyl acetate and quenched withaqueous 1N sodium hydroxide. After partitioning off the aqueous layer,the organic layer was washed with water and brine. It was dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified over a Bakerbond 1 g silica cartridge (Mallinkrodt Baker Inc.Phillipsburg, N.J.) (eluted with 0-5% heptane) to yield 167 mg of acloudy oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 10.91 (s, 1H), 811 (d, J=2.07Hz, 1H), 7.73 (dd, J=8.71, 8.30 Hz, 1H), 7.48 (d, J=7.88 Hz, 1H), 2.96(s, 3H), 2.25 (m, 2H), 2.09 (m, 2H), 1.94-1.57 (m, 8H).

Preparation 24:N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)(3.5bis(trifluoromethyl)phenyl)methanamine

A mixture of 2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzaldehyde(167 mg; 0.556 mmol) and 3,5-bistrifluoromethyl benzylamine (150 mg;0.616 mmol) in toluene (4 mL) was heated at reflux for 16 hours, afterwhich solvent was removed. Ethanol (4 mL) and sodium borohydride (31 mg;0.819 mmol) were added to the residue. The resulting mixture was stirredat room temperature for 16 hours. Solvent was evaporated under reducedpressure. The residue was taken up in ethyl acetate and washed twicewith water and dried over sodium sulfate and concentrated under reducedpressure. The residue was purified over a 12 g RediSep column (TeledyneIsco Inc., Lincoln Nebr.) (eluted with 5-25% ethyl acetate in heptane)to yield 194 mg (66.1% for 2 steps) of the title compound as a gum. MS(ES⁺): Calc: 527.4 Found: 528.4 (M+H).

EXAMPLE 51N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine

To a solution of N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)phenyl)methanamine (181 mg; 0.343 mmol) andsodium acetate trihydrate (100 mg; 0.734 mmoll) in methanol (2 mL) wasadded cyanogen bromide (0.9 mL; 4.5 mmol; 5.0M solution inacetonitrile). Reaction was stirred at room temperature for 16 hours.Solvent evaporated under reduced pressure. The residue was dissolved inethyl acetate and washed twice with water and then with brine. It wasdried over sodium sulfate and concentrated under reduced pressure togive 199 mg (68%) of crude gum. MS (ES−): Calc: 552.4, Found: 551.5(M−H).A mixture of amino-nitrile (197 mg; 0.357 mmol), sodium azide (120 mg;1.84 mmol) and triethylamine hydrochloride (247 mg; 1.79 mmol) intoluene (3 mL) was heated at reflux for 16 hours. The reaction wasdiluted with ethyl acetate and washed twice with water and then brine.The organic was dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by 12 g RediSep column (Teledyne IscoInc., Lincoln Nebr.) (eluted with 20-75% ethyl acetate) to give 145 mg(70% yield for 2 steps) of colorless gum. MS (ES⁺): Calc: 595.5 Found:596.5 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 7.72 (s, 2H),7.52 (m, 2H), 7.35 (s, 1H), 4.92 (s, 4H), 3.15 (bm, 3H), 2.17 (m, 2H),1.98 (m, 2H), 1.86-1047 (m, 8H).

EXAMPLE 52N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

To a solution ofN-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine(145 mg; 0.243 mmol) in 2-methyltetrahydrofuran (2.5 mL) was addedsodium carbonate (110 mg; 1.03 mmol), N,N-dimethylformamide (1.0 mL) anddimethyl sulfate (70 uL; 0.739 mmol). Reaction was stirred for 16 hoursat 60° C. The reaction was diluted with ethyl acetate, washed twice withwater and then brine. The organic was dried sodium sulfate andconcentrated under reduced pressure. The residue was purified by 12 gRediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-30%ethyl acetate in heptane) to give 120 mg (80.9% yield) of a colorlessgum which crystallized into a white solid upon sitting. Melting point:103-104° C. MS (ES+): Calc: 609.5, Found: 610.5 (M+H). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.77 (s, 1H), 7.72 (s, 2H), 7.47 (d, J=7.47 Hz, 1H), 7.46(s, 1H), 7.41 (d, J=8.30 Hz, 1H), 5.10 (s, 2H), 4.79 (s, 2H), 4.20 (s,3H), 2.94 (s, 3H), 2.12 (m, 2H), 1.97 (m, 2H), 1.8-1.46 (m, 8H).

Preparation 25:N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

A mixture of 2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzaldehyde(118 mg, 0.393 mmol) and 2-methyl-2H-tetrazol-5-amine (148 mg, 1.49mmol) in toluene (3 mL) was heated at reflux for 16 hours, after whichsolvent was removed to give a gummy solid. Ethanol (3 mL) and sodiumborohydride (25 mg; 0.660 mmol) were added to the residue. The resultingmixture was stirred at room temperature for 16 hours. Solvent wasevaporated under reduced pressure. The residue was taken up in ethylacetate and washed twice with water and dried over sodium sulfate andconcentrated under reduced pressure. The crude was purified over 4 gRediSep (eluted with 20-60% ethyl acetate in heptane) to give 83 mg (55%yield) of title compound. MS (ES+): Calc: 383.4, Found: 352.3 (M-OMe).¹H NMR (400 MHz, CDCl₃) δ ppm 7.84 (s, 1H), 7.48 (dd, J=8.77 Hz, 1H),7.42 (d, J=8.30 Hz, 1H), 4.92 (d, J=6.22 Hz, 2H), 4.75 (t, J=6.22 Hz,1H), 4.16 (s, 3H), 3.03 (s, 3H), 2.26 (m, 2H), 2.07 (m, 2H), 1.88-1.77(m, 2H), 1.75-1.65 (m, 2H), 1.64-1.52 (m, 4H).

EXAMPLE 533-(((2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-trifluoromethyl)benzonitrile

A mixture ofN-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(75 mg; 0.2 mmol) was stirred in N,N-dimethylformamide (1 mL). To thiswas added sodium hydride (16 mg; 0.4 mmol; 60% dispersion in mineraloil). After stirring at room temperature for 20 minutes, a solution of3-(bromomethyl)-5-(trifluoromethyl)benzonitrile (60 mg; 0.227 mmol) inN,N-dimethylformamide (0.1 mL) was added. The reaction was stirred atroom temperature for 5 hours. More sodium hydride (5 mg; 0.125 mmol; 60%dispersion in mineral oil) was added. Reaction was stirred for 15minutes. The reaction was quenched with water, diluted with ethylacetate and washed with water (2×) and brine. The organic layer wasdried over sodium sulfate and concentrated under reduced pressure. Thecrude was purified over a 4 g RediSep column (Teledyne Isco Inc.,Lincoln Nebr.) (eluted with 10-30% ethyl acetate in hepatane) to give 86mg (78% yield) of the title compound as a gum. MS (ES+): Calc: 566.5,Found: 567.3 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.81 (s, 1H), 7.77 (s,1H), 7.72 (s, 1H), 7.48 (d, J=8.30 Hz, 1H), 7.45 (s, 1H), 7.42 (d,J=8.30 Hz, 1H), 5.12 (s, 2H), 4.75 (s, 2H), 4.21 (s, 3H), 2.95 (s, 3H),2.13 (m, 2H), 2.00 (m, 2H), 1.82-1.62 (m, 4H), 1.62-1.47 (m, 4H).

Preparation 26:(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanone

A mixture of2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzonitrile(445 mg; 0.875 mmol) and cyclohexylmagnesium chloride (1.8 mL; 3.6 mmol;2.0M in diethyl ether) in toluene (7 mL) was heated in a microwavereactor at 66° C. for 50 minutes. The reaction was added to aqueous 2Nhydrochloric acid (30 mL) and stirred at room temperature for 42 hours.Reaction was extracted with ethyl acetate. The organic layer was washedwith water and brine. It was dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified over a 12 g RediSepcolumn (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-35% ethylacetate in heptane) to give 235 mg (45.2%) of a light yellow orange gum.MS (ES+): Calc: 593.4, Found: 594.4 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm7.74 (s, 1H), 7.67 (s, 2H), 7.64 (d, J=8.30 Hz, 1), 7.58 (d, J=7.88 Hz,1H), 7.54 (s, 1H), 4.83 (s, 2H), 4.80 (s, 2H), 4.19 (s, 3H), 3.02 (m,1H), 1.81 (d, J=9.96 Hz, 3H), 1.71 (d J=12.86 Hz, 1H), 1.42-1.18 (m,6H).

Preparation 27:(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol

A solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanone(152 mg; 0.256 mmol) and sodium borohydride (22 mg; 0.582 mmol) inmethanol (1.5 mL) was stirred at room temperature for 16 hours. Thesolvent was evaporated under reduced pressure. The residue was taken upin ethyl acetate, washed twice with water and then brine. The organiclayer was dried sodium sulfate and concentrated under reduced pressure.The residue was purified over 12 g RediSep column (Teledyne Isco Inc.,Lincoln Nebr.) (eluted with 20-50% ethyl acetate in heptane) to give 152mg (99.7% yield) of the title compound as a colorless gum. MS (ES+):Calc: 595.5, Found: 596.1 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.78 (s,1H), 7.66 (s, 2H), 7.57 (d, J=8.30 Hz, 1H), 7.55 (d, J=8.30 Hz, 1H),7.36 (s, 1H), 4.88 (d, J=15.77 Hz, 1H), 4.79 (d, J=15.77 Hz, 1H), 4.76(d, J=15.77 Hz, 1H), 4.70 (d, J=16.18 Hz, 1H), 4.66 (d, J=7.05 Hz, 1H),4.21 (s, 3H), 2.20 (bs, 1H), 1.94 (d, J=12.45 Hz, 1H), 1.78 (m, 1H),1.69-1.51 (m, 4H), 1.2-0.88 (m, 4H).

Preparation 28:(3,5-Bis-trifluoromethyl-benzyl)-[2-(bromo-cyclohexyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol(51 mg; 0.086 mmol) in methylene chloride (1.2 mL) was addedN-bromosuccinimide (63 mg; 0.354 mmol) and triphenylphosphine (97 mg;0.369 mmol). The reaction was stirred at room temperature for 16 hours.Reaction was directly purified over 4 g RediSep column (Teledyne IscoInc., Lincoln Nebr.) (eluted with 10-45% ethyl acetate in heptane) togive 27 mg (48% yield) of the title compound as a colorless gum. MS(ES+): Calc: 657.1, Found: 658.3 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm7.78 (s, 1H), 7.71 (d, J=8.30 Hz, 1H), 7.65 (s, 2H), 7.59 (d, J=8.30 Hz,1H), 7.28 (s, 1H), 4.99 (d, J=9.96 Hz, 1H), 4.91 (d, J=15.35 Hz, 1H),4.68 (q, J=15.77 Hz, 2H), 4.68 (d, J=16.26 Hz, 1H), 4.24 (s, 3H), 2.34(d, J=12.86, 1H), 2.00 (m, 1H), 1.80 (d, 13.28 Hz, 1H), 1.63 (t, J=10.35Hz, 2H), 1.39-1.22 (m, 2H), 1.14 (m, 2H), 0.98 (m, 1H), 0.76 (m, 1H).

EXAMPLE 54(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methylsulfanyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of(3,5-bis-trifluoromethyl-benzyl)-[2-(bromo-cyclohexyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine(26 mg; 0.039 mmol) in THF (1 mL) was added sodium thiomethoxide (8 mg;0.114 mmol). Reaction stirred at room temperature for 16 hours. Reactionwas diluted with ethyl acetate and washed twice with water. The organiclayer was dried sodium sulfate and concentrated to give 23 mg (93%yield) of the title compound as a gum. MS (ES+): Calc: 625.6, Found:626.0 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 7.67 (s, 2H),7.57 (d, J=7.88 Hz, 1H), 7.75-7.56 (bs, 1H), 7.27 (s, 1H), 4.79 (t,J=15.35 Hz, 2H), 4.69 (t, J=15.77 Hz, 2H), 4.23 (s, 3H), 3.81 (bs, 1H),2.21 (d, J=12.86 Hz, 1H), 1.76 (s, 3H), 1.76-1.57 (m, 4H), 1.36 (d,J=12.45 Hz, 1H), 1.25-1.03 (m, 3H), 1.0-0.76 (m, 2H).

EXAMPLE 55(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methanesulfonyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methylsulfanyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine(27 mg; 0.043 mmol) in methylene chloride (1.0 mL) was addedmeta-chloroperbenzoic acid (17 mg; 0.098 mmol). The reaction was stirredat room temperature for 16 hours. After adding saturated aqueous sodiumbicarbonate (2 drops), the reaction was stirred for 15 minutes. Theresulting mixture was filtered over sodium sulfate and concentratedunder reduced pressure The residue was purified over 4 g RediSep column(Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-40% ethyl acetate inheptane) to give 16.5 mg (58% yield) of the title compound as a gum. MS(ES+): Calc: 657.6, Found: 658.5 (M+H). 1H NMR (400 MHz, CDCl₃) δ ppm7.89 (d, J=8.3 Hz, 1H), 7.84 (s, 1H), 7.70 (s, 2H), 7.67 (d, J=8.3 Hz,1H, 7.34 (s, 1H), 4.91 (d, J=15.77 Hz, 1H), 4.83 (d, J=16.18 Hz, 1H),4.62 (d, J=14.11 Hz, 1H), 4.58 (d, J=15.77 Hz, 1H), 4.52 (d, J=8.3 Hz,1H), 4.24 (s, 3H), 2.58 (s, 3H), 2.39 (m, 2H), 1.78 (d, J=14.11 Hz, 1H),1.63 (t, J=12.86, 12.03 Hz. 2H), 1.4-1.05 (m, 5H), 0.79 (m, 1H).

Preparation 29: Cyclobutylmagnesium bromide

To a suspension of magnesium granules (210 mg; 8.64 mmol) and iodine (54mg, 0.212 mmol) in dimethoxyethane (3.5 mL) was added cyclobutyl bromide(0.2 mL; 2.12 mmol) with stirring in an oil bath at 50° C. Iodomethane(0.05 mL; 0.8 mmol) was added followed by cyclobutyl bromide (0.2 mL;2.12 mmol). An additional aliquot of iodomethane (0.1 ml; 1.6 mmol) wasadded then the reaction was stirred at 50° C. for 1.5 hours beforeallowing to cool to room temperature. The concentration ofcyclobutylmagnesium bromide was determined using the method described byLove, B. E. and Jones, E. G., Journal of Organic Chemistry, 1999, 64,3755 as follows.To a solution of salicylaldehyde phenylhydrazone (80 mg; 0.376 mmol) intetrahydrofuran (10 mL) at room temperature was added thecyclobutylmagnesium bromide solution dropwise. The endpoint, indicatedby a color change from yellow to orange, was reached after the additionof 0.62 mL of the cyclobutylmagnesium bromide solution, indicating amolarity of 0.6M.

Preparation 30:(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-trifluoromethyl)phenyl)(cyclobutyl)methanone

To a solution of(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amine(Preparation 6, 0.5 mmol, 281 mg) in anhydrous THF was addedisopropylmagnesium chloride/lithium chloride in THF (0.72M, 1.5 mmol,2.1 mL, prepared according to the procedure described in Angew. Chem.Int. Ed. 2004, 43, 3333). The mixture was cooled to 0° C. and stirredfor 3 hours before cooling to −78° C. To this was added a solution ofCuCN.2LiCl in THF (1M, 0.5 mmol, 0.5 mL, solution prepared by stirring 1equivalent of CuCN with 2 equivalents of freshly dried LiCl in anhydrousTHF (1 mL per equivalent) until all of the solid was dissolved). After30 minutes at −78° C., a solution of cyclobutylcarbonyl chloride (1.5mmol, 178 mg) in anhydrous THF (2 mL) was added and the mixture wasallowed to warm to room temperature before pouring into an aqueoussolution of ammonium chloride to which some ammonium hydroxide had beenadded. This mixture was filtered through Celite® and extracted withdichloromethane (2×). The organic layer was dried with anhydrous sodiumsulfate and evaporated to dryness under reduced pressure. The residuewas purified by silica chromatography using a 12 g RediSep column(Teledyne Isco Inc., Lincoln Nebr.) (eluted with 0-65% ethyl acetate inheptane) to give the title compound (81.7 mg, 29%) MS (ES+): Calc:565.4, Found: 566.4 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.75 (s, 1H),7.68 (s, 2H), 7.66 (d, J=8.71 Hz, 1H), 7.56 (d, J=9.54 Hz, 2H), 5.00 (s,2H), 4.84 (s, 2H), 4.19 (s, 3H), 3.88 (m, 1H), 2.4-1.2.1 (m, 4H),2.1-1.2.0 (m, 1H), 1.96-1.8 (m, 1H).

Preparation 31:(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl-cyclobutyl-methanol

To a solution of2-{[(3,5-bis-trifluoromethyl-benzyl)(2-methyl-2H-tetrazol-5-yl)amino]-methyl}-4-trifluoromethyl-benzaldehyde(1.5 g; 2.9 mmol) in tetrahydrofuran (14 mL) at −10° C. was addeddropwise cyclobutylmagnesium bromide (9 mL; 5.4 mmol; 0.6M solution intetrahydrofuran). The reaction was stirred at −10° C. for 1.5 hours. Toquench the reaction, at 0° C. was added aqueous 2N hydrochloric acid.Reaction extracted with ethyl acetate. The organic was washed withaqueous 2N hydrochloric acid, water and brine. It was dried sodiumsulfate and concentrated under reduced pressure. The residue waspurified by 40 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.)(eluted with 15-70% ethyl acetate in heptane) to give 420 mg (25% yield)as a gum. MS (ES−): Calc; 567.4, Found: 612.6 (M+HCO₂). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.78 (s, 1H), 7.66 (s, 2H), 7.52 (d, J=8.30 Hz, 1H), 7.49(d, J=8.30 Hz, 1H), 7.35 (s, 1H), 4.86 (q, J=15.77 Hz, 2H), 4.86 (s,1H), 4.77 (q, J=15.77, 16.18 Hz, 2H), 4.20 (s, 3H), 2.68 (m, 1H),2.05-1.96 (m, 2H), 1.93-1.76 (m, 3H), 1.70 (m, 1H).

EXAMPLE 56(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclobutyl-ethoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclobutyl-methanol(23 mg; 0.041 mmol) in THF (1.5 mL) at 0° C. was added sodium hydride(15 mg; 0.375 mmol; 60% dispersion in mineral oil). After stirring atroom temperature for 30 minutes ethyl iodide (0.05 mL; 0.625 mmol) wasadded. Reaction was stirred for 2 hours. More sodium hydride (15 mg;0.375 mmol; 60% dispersion in mineral oil) and iodoethane (0.05 mL;0.625 mmol) were added. Reaction stirred for 72 hours. Reaction wasquenched with 2 drops of water. The reaction was filtered over a 1 gBakerbond silica cartridge (Mallinkrodt Baker Inc. Phillipsburg, N.J.)(eluted with ethyl acetate). The crude was purified by RediSep column(Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-30% ethyl acetate inheptane) to give 21 mg (87% yield) of a gum. MS (ES+): Calc: 595.5,Found: 596.4 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.78 (s, 1H), 7.65 (s,2H), 7.53 (s, 2H), 7.33 (s, 1H), 4.83 (q, J=16.18 Hz, 2H), 4.73 (q,J=16.18, 14.11 Hz, 2H), 4.42 (d, J=6.64 Hz, 1H), 4.22 (s, 3H), 3.20 (m,J=7.05, 6.64 Hz, 2H), 2.49 (m, J=7.88, 7.05 Hz, 1H), 2.07-1.57 (m, 6H),1.11 (t, J=7.05 Hz, 3H).

EXAMPLE 57N-(2-(1-methoxy-2,2-dimethylpropyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

The title compound was prepared in an analogous manner to that describedfor the preparation of(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclobutyl-ethoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)aminefrom2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehydeby the addition of tert-butylmagnesium chloride followed byO-methylation with methyl iodide.

LC-MS (ES−): Calc: 583.4, Found: 628 (M+HCO₂ ⁻)

EXAMPLES 58 AND 59(R)—N-(2-(cyclobutyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amineand(S)—N-(2-cyclobutyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

The enantiomers of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclobutyl-methanolwere separated as follows. The racemic mixture of the alcohol (431 mg)was dissolved in methanol, injected onto a Chiralpak AD column (10 cm×50cm) (Chiral Tech Inc. Westchester, Pa., USA) and eluted usingheptane/2-propanol (96:4, 475 mL/minute). Enantiomer 1 (170 mg, 100% ee)eluted at 9.880 minutes, and enantiomer 2 (163 mg, 95.8% ee) eluted at11.200 minutes on a Chiralpak AD-H column. Each enantiomer was convertedto the title compound using an O-methylation procedure analogous to thatused for the preparation of(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-4-methyl-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine.Enantiomer 1 (from the 9.88 minute peak): [α]_(D) ²⁰=+38.02° (c 0.0142g/ml, methanol). Enantiomer 2 (from the 11.2 minute peak): [α]_(D)²⁰=−35.88° (c 0.0119 g/ml, methanol). MS (ES+): Calc: 581.4, Found:582.5 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 7.66 (s, 2H),7.55 (d, J=8.30 Hz, 1H), 7.50 (d, J=8.30 Hz, 1H), 7.35 (s, 1H), 4.82 (q,J16.18 Hz, 2H), 4.73 (s, 2H), 4.34(d, J=7.05 Hz, 1H), 4.23 (s, 3H), 3.12(s, 3H), 2.50 (m, 1H), 2.04-1.85 (m, 2H), 1.83-1.61 (m, 4H).

Preparation 32:1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-1-cyclobutylethanol

To a solution of(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(cyclobutyl)methanone(Preparation 29, 28 mg; 0.050 mmol) in tetrahydrofuran (0.5 mL) wasadded methylmagnesium bromide (50 uL; 0.15 mmol; 3.0M in diethyl ether).The reaction was stirred at room temperature for 2 hours. The reactionwas quenched with 2 drops water and 1 drop aqueous 2N hydrochloric acid.The mixture was diluted with ethyl acetate and filtered over a columncontaining silica gel and sodium sulfate. The crude was purified over 4g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-50%ethyl acetate in heptane) to give 22 mg (76% yield) of the titlecompound as a colorless gum. MS (ES−): Calc: 581.4, Found: 580.6 (M−H).¹H NMR (400 MHz, CDCl₃) δ ppm 7.78 (s, 1H), 7.74 (s, 2H), 7.42 (d, 1H),7.41 (s, 1H), 7.33 (d, J=9.13 Hz, 1H), 5.27(d, J=16.60 Hz, 1H), 5.15 (d,J=16.18 Hz, 1H), 4.85 (s, 2H), 4.18 (s, 3H), 2.97 (m, 1H), 2.12-1.69 (m,6H), 1.43 (s, 3H).

EXAMPLE 60N-(2-(1-cyclobutyl-1-methoxyethyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

To a solution of1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-1-cyclobutylethanol(22 mg; 0.038 mmol) in tetrahydrofuran (1.5 mL) was added sodium hydride(10 mg; 0.25 mmol; 60% dispersion in mineral oil). The reaction wasstirred for 10 minutes. Iodomethane (0.05 mL; 0.80 mmol) was added. Thereaction was stirred at room temperature for 16 hours. The reaction wasquenched with water. The mixture was diluted with ethyl acetate andfiltered over sodium sulfate and silica get column. After beingconcentrated under reduced pressure, the residue was taken up in ethylacetate and washed with water (2×) and brine. The organic layer wasdried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified over a 4 g RediSep column (Teledyne Isco Inc.,Lincoln Nebr.) (eluted with 10-50% ethyl acetate in hexanes) to give 18mg (80% yield) of the title compound as a colorless gum. MS (ES+): Calc:595.5, Found: 596.5 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.78 (s, 1H),7.73 (s, 2H), 7.45 (d, J=8.3 Hz, 1H), 7.43 (s, 1H), 7.3 (d, J=8.3 Hz,1H), 5.09 (s, 2H), 4.8 (q, J=16.18 Hz, 2H), 4.2 (s, 3H), 3.04 (s, 3H),2.83 (m, 1H) 1.99 (m, 1H), 1.89-1.6 (m, 6H), 1.59 (s, 3H).

Preparation 33:1-(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-1-cyclohexyl-ethanol

To a solution of(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanone(143 mg; 0.241 mmol) in tetrahydrofuran (2.5 mL) at 0° C. was added 3.0Mmethylmagnesium bromide in tetrahydrofuran (0.25 mL; 0.75 mmol). After15 minutes, the bath was removed and reaction was stirred at roomtemperature for 3 hours. The reaction was quenched with 2 drops ofwater. The reaction was diluted with ethyl acetate and dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified over 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.)(eluted with 10-50% ethyl acetate in heptane) to give 158 mg (108%yield) of a colorless oil. MS (ES+): Calc: 609.5, Found: 610.4 (M+H). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.77 (s, 1H), 7.74 (s, 1H) 7.42 (m, 2H), 7.34(d, J=8.30 Hz, 1H), 5.46 (d, J=16.18 Hz, 1H), 4.93 (d, J=16.60 Hz, 1H),4.82 (q, J=16.18 Hz, 2H), 4.18 (s, 3H), 1.78-1.6 (m, 6H), 1.58 (s, 3H),1.40 (m, 1H), 1.13-0.94 (m, 4H).

EXAMPLE 61(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-cyclohexyl-1-methoxy-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

To a solution of1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-1-cyclohexylethanol(26 mg; 0.043 mmol) in tetrahydrofuran (0.7 mL) was added sodium hydride(11 mg; 0.275 mmol; 60% dispersion in mineral oil). After stirring for30 minutes at room temperature, iodomethane (30 uL; 0.485 mmol) wasadded. The reaction was stirred for 16 hours. More sodium hydride (12mg; 0.3 mmol; 60% dispersion in mineral oil) and iodomethane (30 uL;0.485 mmol) were added. After 1 hour more sodium hydride (12 mg; 0.3mmol; 60% dispersion in mineral oil) was added. After 30 minutes,iodomethane (30 uL; 0.485 mmol) was added. The reaction was stirred for2 hours. The reaction was quenched with aqueous 2N hydrochloric acid (6drops). The mixture was diluted with ethyl acetate and filtered oversodium sulfate/silica plug. Then the solution was concentrated. Theresidue was purified by 4 g RediSep column (Teledyne Isco Inc., LincolnNebr.) (eluted with 5-25% ethyl acetate in heptane) to give 19 mg (71%yield) of a colorless gum. MS (ES+): Calc: 623.5, Found: 592.5 (M-OCH₃).¹H NMR (400 MHz, CDCl₃) δ ppm 7.78 (s, 1H), 7.73 (s, 2H), 7.46 (s, 1H),7.45 (d, J=7.47 Hz, 1H), 7.27 (d, J=8.30 Hz, 1H), 5.25 (d, J=17.43 Hz,1H), 5.07 (d, J=17.43 Hz, 1H), 4.79 (q, J=16.60, 16.18 Hz, 2H), 4.19 (s,3H), 3.02 (s, 3H), 2.01 (d, J=11.2 Hz, 1H), 1.78-1.67 (m, 2H), 1.66-1.55(m, 2H), 1.53 (s, 3H), 1.11-0.83 (m, 6H).

EXAMPLES 62 AND 63 Separation ofIsomers-(S)—N-(2-(1-cyclohexyl-1-methoxyethyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amineAND(R)—N-(2-(1-cyclohexyl-1-methoxyethyl)-5-trifluoromethyl)benzyl)-N-3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

The enantiomers of Example 61 were prepared as follows. The racemicmixture of the alcohol (Preparation 33, 154 mg) was dissolved inmethanol, injected onto a Chiralpak AD column (10 cm×50 cm) (Chiral TechInc. Westchester, Pa., USA) and eluted using heptane/2-propanol (96:4,475 mL/minute). Enantiomer 1 (91 mg, 100% ee) eluted at 4.429 minutes,and enantiomer 2 (85 mg, 100% ee) eluted at 5.513 minutes on a ChiralpakAD-H column. Each enantiomer was converted to the title compoundaccording to the procedure analogous to that used for the preparation ofExample 61. Enantiomer 1 (from earlier eluting alcohol): [α]_(D)²⁰=+17.56° (c=0.00705 g/mL, methanol). Enantiomer 2 (from later elutingalcohol): [α]_(D) ²⁰=−17.41° (c=0.0065 g/mL, methanol). MS (ES+): Calc:623.5, Found: 592.5 (M-OCH³). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.78 (s,1H), 7.73 (s, 2H), 7.46 (s, 1H), 7.45 (d, J=7.47 Hz, 1H), 7.27 (d,J=7.88 Hz, 1H), 5.25 (d, J=17.43 Hz, 1H), 5.07 (d, J=17.84 Hz, 1H), 4.84(d, J=16.18 Hz, 1H), 4.73 (d, J=16.6 Hz, 1H), 4.19 (s, 3H), 3.02 (s,3H), 2.01 (d, J=11.62 Hz, 1H), 1.78-1.67 (m, 2H), 1.66-1.55 (m, 2H),1.53 (s, 3H), 1.11-0.89 (m, 3H).

Preparation 34: tert-Butyl4-(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)-4-hydroxypiperidine-1-carboxylate

To a solution of(2-bromo-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (904mg; 2.45 mmol) in tetrahydrofuran (6.0 mL) at −78° C. was added dropwisen-butyllithium (1.5 mL; 3.75 mmol: 2.5M in hexanes). The reaction wasstirred at −78° C. for 5 minutes. Then a solution of Boc-piperidone (831mg; 4.17 mmol) in tetrahydrofuran (3 mL) was added dropwise intoreaction. During addition reaction turned yellow in color. The reactionwas stirred at −78° C. allowing it to warm to −40° C. within 1 hour. Thereaction was quenched with water and extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous ammonium chloride, waterand brine. The organic layer was dried sodium sulfate and concentratedunder reduced pressure. The residue was purified over 40 g RediSepcolumn (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-15% ethylacetate in heptane) to give 526 mg (43.9% yield) of a white solid. MS(ES+): Calc. 489.6, Found: 534.6 (M−HCO₃). ¹H NMR (400 MHz, CDCl₃) δ ppm7.54 (dd, J=8.30, 8.71 Hz, 1H), 7.49 (d, J=1.66 Hz, 1H), 7.40 (d, J=8.30Hz, 1H), 5.02 (s, 2H), 4.78 (s, 1H), 4.04 (d, J=16.18 Hz, 2H), 3.28 (dt,J=12.86, 2.90, 13.28, 2H), 2.00 (dt, J=12.86, 13.28, 4.98, 4.56, 2H),1.84 (d, J=12.45 Hz, 2H), 1.50 (s, 9H), 0.92 (s, 9H), 0.13 (s, 6H).

Preparation 35: tert-Butyl4-(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate

To a solution of tert-butyl4-(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)-4-hydroxypiperidine-1-carboxylate(526 mg; 1.07 mmol) in tetrahydrofuran (6 mL) at 0° C. was added sodiumhydride (75 mg; 60% dispersion in mineral oil). The reaction was stirredfor 10 minutes. Then iodomethane (0.10 mL; 1.61 mmol) was added. Thereaction was stirred for 72 hours at room temperature. The reaction wasquenched with water and 2N hydrochloric acid. The reaction was extractedwith ethyl acetate. The organic layer was washed with water and brine.It was dried sodium sulfate and concentrated under reduced pressure. Theresidue was purified by 40 g RediSep column (Teledyne Isco Inc., LincolnNebr.) (eluted with 5-20% ethyl acetate in heptane) to give 540 mg(99.8% yield) of a colorless gum. MS (ES+): Calc: 503.6, Found: 445.4(M−¹BuH). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.08 (s, 1H), 7.49, (dd, J=7.88,8.30 Hz, 1H), 7.31 (d, J=8.30 Hz, 1H), 5.03 (s, 2H), 4.03 (bs, 2H), 3.16(bs, 2H), 2.97 (s, 3H), 2.15 (d, J=12.86 Hz, 2H), 1.85 (bs, 2H), 1.48(s, 9H), 0.98 (s, 9H), 0.14 (s, 6H).

Preparation 36: tert-Butyl4-(2-hydroxymethyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate

A solution of tert-butyl4-(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate(540 mg; 1.07 mmol) and tetrabutylammonium fluoride (1.7 mL; 1.7 mmol;1.0M in tetrahydrofuran) in tetrahydrofuran (6 mL) was stirred at roomtemperature for 2 hours. The solvent was evaporated under reducedpressure. The residue was purified by 40 g RediSep column (Teledyne IscoInc., Lincoln Nebr.) (eluted with 10-90% ethyl acetate in heptane) togive 414 mg (99.2% yield) as a colorless gum. MS (ES+): Calc: 389.4,Found: 390.3 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.92 (s, 1H), 7.53 (d,J=8.30 Hz, 1H), 7.36 (d, J=8.30 Hz, 1H), 5.04 (s, 2H), 4.02 (d, J=12.45Hz, 2H), 3.19 (t, J=12.45 Hz, 2H), 3.00 (s, 3H), 2.39 (bs, 1H), 2.24 (d,J=14.11 Hz, 2H), 1.86 (dt, J13.28, 4.15, 4.56 Hz, 2H), 1.48 (s, 9H).

Preparation 37: tert-Butyl4-(2-(bromomethyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate

To a solution of tert-butyl4-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate(410 mg, 1.05 mmol) in methylene chloride (7 mL) were addedN-bromosuccinimide (342 mg; 1.92 mmol) and triphenylphosphine (516 mg;1.96 mmol). The reaction was stirred at room temperature for 1 hour. Thereaction was then purified over 40 g RediSep column (Teledyne Isco Inc.Lincoln Nebr.) (eluted with 5-30% ethyl acetate in heptane) to give 433mg (90% yield) of a colorless oil. MS (ES+). Calc: 452.3 (⁸¹Br), Found:407.2 (M(⁸¹Br)—HCO₂ ⁻). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.82 (d, J=1.66Hz, 1H), 7.52 (dd, J=8.30, 1.66 Hz, 1H), 7.34, (d, J=8.30 Hz, 1H), 5.08(s, 2H), 4.04 (d, J=12.86 Hz, 2H), 3.21 (t, J=12.86, 13.28 Hz, 2H), 3.02(s, 3H), 2.26 (d, J=14.11 Hz, 2H), 1.86 (t, J=12.86, 14.11 Hz, 2H), 1.48(s, 9H).

EXAMPLE 64 tert-butyl 4-(2-(((3,5-bis(trifluoromethylbenzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate

To a solution ofN-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (432 mg;1.32 mmol)) in tetrahydrofuran (5.0 mL) was added dropwise 1.0Mpotassium t-butoxide in tetrahydrofuran (1.1 mL). The reaction wasstirred for 5 minutes. A solution of tert-butyl4-(2-(bromomethyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate(432 mg; 0.955 mmol) in tetrahydrofuran (0.7 mL) was added dropwise toreaction. The reaction was stirred at room temperature. The reaction wasquenched with water and extracted with ethyl acetate. The organic layerwas washed with water and brine. It was then dried with sodium sulfateand concentrated under reduced pressure. The residue was purified over40 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with10-50% ethyl acetate in heptane) to give 371 mg (55.8% yield) of acolorless gum. MS (ES+): Calc: 696.6, Found: 697.4 (M+H). ¹H NMR (400MHz, CDCl₃) δ ppm 7.79 (s, 1H), 7.73 (s, 2H), 7.51 (m, 2H), 7.37 (d,J=8.71 Hz, 1H), 5.10 (s, 2H), 4.81 (s, 2H), 4.20 (s, 3H), 4.0 (bs, 2H),3.12 (bs, 2H), 2.95 (s, 3H), 2.12, (bs, 2H), 1.82 (bs, 2H), 1.47 (s,9H).

EXAMPLE 65N-(2-(4-methoxypiperidine-4-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

To a solution of tert-butyl4-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate(321 mg; 0.461 mmol) in 1,4-dioxane (2.5 mL) was added 4.0M hydrogenchloride in 1,4-dioxane (0.5 mL; 2 mmol). The reaction was stirred atroom temperature for 2 hours. 4.0M hydrogen chloride in 1,4-dioxane (1.5mL; 6 mmol) was added and stirred for 1 hour. 4.0M hydrogen chloride in1,4-dioxane (1.5 mL; 6 mmol) was added and stirred for 1 hour. Thesolvent was evaporated under reduced pressure. Ethyl acetate was addedto the residue and was concentrated under reduced pressure. Isopropylether was added and let sit for 16 hours. The solvent was evaporatedunder reduced pressure to give a white solid. The white solid wastriturated with isopropyl ether and filtered off to give 254 mg (87.1%yield) of a white solid. MS (ES+): Calc: 596.4, Found: 597.4 (M+H). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.92 (s, 2H), 7.87 (s, 1H), 7.59 (d, J=8.30Hz, 1H), 7.54(d, J=7.88 Hz, 1H), 7.45 (s, 1H), 5.14 (s, 2H), 4.96 (s,2H), 4.19 (s, 3H), 3.35 (m, 4H), 3.03 (s, 3H), 2.56(d, J=12.86 Hz, 2H),2.14 (m, 2H).

EXAMPLE 66 Methyl4-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)aminomethyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate

To a suspension ofN-2-(4-methoxypiperidin-4-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(31 mg; 0.049 mmol) in methylene chloride (0.5 mL) was addeddiisopropylethylamine (0.05 mL; 0.287 mmol). Methyl chloroformate (10uL; 0.129 mmol) was then added. The resulting reaction was stirred atroom temperature for 16 hours. The reaction was filtered over a columnof silica/sodium sulfate and concentrated under reduced pressure. Theresidue was purified by 4 g RediSep column (Teledyne Isco Inc., LincolnNebr.) (5-80% ethyl acetate in heptane) to give 32 mg (100%) of a gum.MS (ES+): Calc: 654.5, Found: 655.5 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm7.79 (s, 1H), 7.73 (s, 2H), 7.50 (d, J=7.05 Hz, 1H), 7.49 (s, 1H), 7.36(d, J=8.71 Hz, 1H), 5.10 (s, 2H), 4.82 (s, 2H), 4.2 (s, 3H), 4.02 (bm,2H), 3.71 (s, 3H), 3.17 (t, J=12.45, 12.03 Hz, 2H), 2.95 (s, 3H), 2.14(m, 2H), 1.9-1.75 (m, 2H).

EXAMPLE 67 Ethyl4-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate

To a suspension ofN-(2-(4-methoxypiperidin-4-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(31 mg; 0.049 mmol) in methylene chloride (0.5 mL) was addeddiisopropylethylamine (0.05 mL; 0.287 mmol). Ethyl chloroformate (10uL;0.104 mmol) was then added. The resulting reaction was stirred at roomtemperature for 16 hours. The reaction was filtered over a column ofsilica/sodium sulfate and concentrated under reduced pressure. Theresidue was purified by 4 g RediSep column (Teledyne Isco Inc., LincolnNebr.) (30-85% ethyl acetate in heptane) to give 32 mg (98%) of a gum.MS (ES+): Calc: 668.5, Found: 669.6 (M+H), ¹H NMR (400 MHz, CDCl₃) δ ppm7.79 (s, 1H), 7.73 (s, 2H), 7.51 (d, J=6.64 Hz, 1H), 7.50 (s, 1H), 7.36(d, J=8.71 Hz, 1H), 5.10 (s, 2H), 4.82 (s, 2H), 4.2 (s, 3H), 4.14 (q,J=7.05, 2H), 4.02 (bm, 2H), 3.16 (t, J=12.45 Hz, 2H), 2.95 (s, 3H), 2.14(m, 2H), 1.9-1.63 (m, 2H), 1.27 (t, J=7.05 Hz, 3H).

Preparation 38:1-(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)cyclohexanol

To a solution of(2-bromo-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (140mg; 0.379 mmol) in tetrahydrofuran (0.5 mL) at −78° C. was addeddropwise n-butyllithium (0.4 mL; 0.64 mmol; 1.6M in hexanes). Thereaction was stirred at −78° C. for 15 minutes. Cyclohexanone (0.8 mL;7.7 mmol) was added stirred at −78° C. for 10 minutes. The reaction wasthen stirred at room temperature for 15 minutes. The reaction wasquenched with 2 drops of water. It was diluted with ethyl acetate andfiltered through a column containing silica gel and sodium sulfate. Thecrude was then purified over a 12 g RediSep column (Teledyne Isco Inc.,Lincoln Nebr.) (eluted with 10-40% ethyl acetate in heptane) to give 112mg (76%) as a liquid. MS (ES+): Calc: 388.5, Found: 433.2 (M+HCO₂ ⁻) ¹HNMR (400 MHz, CDCl₃) δ ppm 7.58 (s, 1H), 7.51 (d, J=8.30 Hz, 1H), 7.45(d, J=8.30 Hz, 1H), 5.05 (s, 2H), 3.92 (s, 1H), 1.94-1.73 (m, 6H),1.68-1.6 (m, 2H), 1.31 (m, 2H), 0.93 (s, 9H), 0.12 (s, 6H).

Preparation 39:(2-(1-methoxycyclohexyl)-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane

To a solution of1-(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)cyclohexanol(108 mg; 0.278 mmol) in tetrahydrofuran (2 mL) at 0° C. was added sodiumhydride (22 mg; 0.55 mmol). The reaction was stirred at 0° C. for 30minutes. Then iodomethane (50 uL; 0.80 mmol) was added. The reaction wasstirred at 0° C. for 30 minutes and then at room temperature for 16hours. More iodomethane (20 uL; 0.32 mmol) was added and stirred for 4hours. The reaction was quenched with water and extracted with ethylacetate. The organic layer was washed with water, dried over sodiumsulfate, and concentrated under reduced pressure. The crude was purifiedover a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (elutedwith 5-15% ethyl acetate in heptane) to give 63 mg (55%) the titlecompound as a colorless oil. MS-GC (El): Calc: 402.5, Found: 383 (M−F).¹H NMR (400 MHz, CDCl₃) δ ppm 7.51 (d, J=7.88 Hz, 1H), 7.46 (d, J=7.47Hz, 1H), 7.35 (d, J=8.30 Hz, 1H), 5.05 (s, 2H), 2.94 (s, 3H), 2.16 (d,J=12.45 Hz, 2H), 1.8-1.56 (m, 8H), 0.98 (s, 9H), 0.13 (s, 6H).

Preparation 40:(2-(1-methoxycyclohexyl)-5-(trifluoromethyl)phenyl)methanol

A solution of(2-(1-methoxycyclohexyl)-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane(61 mg, 0.15 mmol) and tetrabutylammonium fluoride (0.2 mL; 0.2 mmol;1.0M in tetrahydrofuran) was stirred in tetrahydrofuran (1 mL). Thereaction was stirred at room temperature for 3 hours. The solvent wasevaporated under reduced pressure. The residue was purified by 4 gRediSep column (Teledyne Isco inc., Lincoln Nebr.) (eluted with 10-40%ethyl acetate in heptane) to give 30 mg (69% yield) of a colorless gum.MS-GC (El): Calc: 288.3, Found: 288 (M). ¹H NMR (400 MHz, CDCl₃) δ ppm7.87 (s, 1H), 7.50 (d, J=8.30 Hz, 1H), 7.41 (d, J=8.30 Hz, 1H), 5.03 (s,2H), 2.99 (s, 3H), 2.24 (d, J=13.28 Hz, 2H), 1.8-1.57 (m, 7H), 1.28 (m,1H).

Preparation 41:2-(bromomethyl)-1-(1-methoxycyclohexyl)-4-(trifluoromethyl)benzene

To a solution of(2-(1-methoxycyclohexyl)-5-(trifluoromethyl)phenyl)methanol (27 mg;0.094 mmol) in methylene chloride (1 mL) was added N-bromosuccinimide(28 mg; 0.157 mmol) followed by triphenylphosphine (40 mg; 0.152 mmol).The reaction was stirred at room temperature for 4 hours. The reactionwas directly loaded onto silica and purified over 4 g RediSep column(Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-40% ethyl acetate inheptane) to give 26 mg (79%) of a gum. MS-GC (El): Calc: 351.2, Found;352 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.81 (d, J=1.66 Hz, 1H), 7.48(td, J=8.30, 1.66 Hz, 1H), 7.39 (d, J=8.30 Hz, 1H), 5.12 (s, 2H), 3.00(s, 3H), 2.25 (d, J=12.45 Hz, 2H), 1.84-1.71 (m, 3H), 1.65 (m, 4H),1.27(m, 1H).

EXAMPLE 68N-(2-(1-methoxycyclohexyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

To a solution ofN-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (26 mg;0.079 mmol) in tetrahydrofuran (0.3 mL) was added potassium t-butoxide(80 uL; 0.08 mmol; 1.0M in tetrahydrofuran). A solution of2-(bromomethyl)-1-(1-methoxycyclohexyl)-4-(trifluoromethyl)benzene (25mg; 0.071 mmol) in tetrahydrofuran (0.2 mL) was added. The reaction wasstirred at room temperature for 3 hours. The reaction was quenched with2 drops of water. The mixture was diluted with ethyl acetate andfiltered through a column containing silica and sodium sulfate andconcentrated. The residue was purified by 4 g RediSep column (TeledyneIsco Inc., Lincoln Nebr.) (eluted with 10-45% ethyl acetate in heptane)to give 25 mg (59%) of a colorless gum. MS (ES+): Calc: 595.5, Found:596 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.77 (s, 1H), 7.73 (s, 2H),7.48 (d, J=7.47 Hz, 2H), 7.42 (d, J=8.30 Hz, 1H), 5.14 (s, 2H), 4.79 (s,2H), 4.20 (s, 3H), 2.92 (s, 3H), 2.12 (d, J=11.62 Hz, 2H), 1.77-1.52(m,8H).

Preparation 42:2-(((3,5-bis(triflouromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)benzonitrile

A mixture ofN-(2-bromo-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(10.4 g; 18.5 mmol), potassium hexacyanoferrate trihydrate (1.9 G; 4.49mmol) and sodium carbonate (2.4 g; 22.6 mmol) was stirred inN,N-dimethylacetamide (32 mL). Palladium acetate was added (0.48 g; 2.13mmol). The reaction was stirred at 120° C. for 16 hours. The reactionwas diluted with diethyl ether and filtered over a pad of silica gel andcelite. The mother liquor was washed with water (3×) and brine. It wasdried over sodium sulfate and concentrated under reduced pressure. Thecrude was purified over a 330 g RediSep column (Teledyne Isco Inc.,Lincoln Nebr.) (eluted with 10-30% ethyl acetate in heptane) to give8.45 g (89.9%) of title compound as a tan solid. MS (ES+): Calc: 508.3,Found: 509.2 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.76 (s, 1H), 7.75 (d,J=8.30 Hz, 1H), 7.68 (s, 3H), 7.62 (dd, J=8.30 Hz, 1H), 4.96 (s, 2H),4.89 (s, 2H), 4.22 (s, 3H).

EXAMPLE 69N-(2-(methoxy(1-methylcyclohexyl)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

Step A: 2-bromo-5-(trifluoromethyl)benzyl-1-methylcyclohexanecarboxylate

To a mixture of 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene(Preparation 3, 0.97 g, 3.05 mmol) and 1-methylcyclohexanecarboxylicacid (0.512 g, 3.6 mmol) in N,N-dimethylformamide (5 mL) was addedcesium carbonate (1.96 g, 6 mmol) and sodium iodide (90 mg, 0.6 mmol).The mixture was heated at 60° C. for 5 hours, diluted with water andextracted with dichloromethane (3×). The combined organic layers weredried over sodium sulfate and concentrated to dryness under vacuum. Theresidue was purified by flash chromatography on a 40 g RediSep column(Teledyne Isco Inc., Lincoln Nebr.) (eluted with 0-30% ethyl acetate inheptane) to yield the title compound as a yellow oil (0.65 g). ¹H NMR(400 MHz, CDCl₃) δ 7.71 (d, J=8.3 Hz, 1H), 7.65 (d, J=1.2 Hz, 1H), 7.45(dd, J=8.3, 1.2 Hz, 1H), 5.23 (s, 2H), 2.10 (m, 2H), 1.64-1.48 (m, 2H),1.46-1.21 (m, 6H), 1.24 (s, 3H).

GC-MS (El) Calc: 380 (⁸¹Br), Found: 380 (⁸¹Br)

Step B:1-(1-methylcyclohexyl)-5-(trifluoromethyl)-1,3-dihydroisobenzofuran-1-oland(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)(1-methylcyclohexyl)methanone

To a solution of 2-bromo-5-(trifluoromethyl)benzyl1-methylcyclohexanecarboxylate (0.432 g, 1.14 mmol) in tetrahydrofuran(5 mL) under N₂ at −98° C. was slowly added s-butyllithium (1.4M incyclohexane, 1.37 mmol, 0.98 mL). After stirring at −98° C. for 90minutes the mixture was warmed to −78° C. for 10 minutes then allowed towarm to 0° C. The mixture was then immediately poured into an aqueousammonium chloride solution and extracted with dichloromethane (3×). Thecombined organic layers were dried over sodium sulfate and concentratedto dryness under vacuum. The residue was purified by flashchromatography on a 40 g RediSep column (Teledyne Isco Inc., LincolnNebr.) (eluted with 0-30% ethyl acetate in heptane) to yield a whitesolid which in deuterochloroform solution existed as a mixture of thetitle compounds in a ratio of approximately 12:1 respectively. ¹H NMR(400 MHz, CDCl₃)(major component) δ 7.61 (d, J=8.3 Hz, 1H), 7.58 (d,J=8.3 Hz, 1H), 7.50 (s, 1H), 5.18 (d, J=13.1 Hz, 1H), 5.03 (d, J=13.1Hz, 1H), 2.77 (s, 1H), 1.7-1.49 (m, 6H), 1.49-1.31 (m, 4H), 1.08 (s,3H). GC-MS (El) Calc: 300, Found: 300

Step C:(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)(1-methylcyclohexyl)methanol

The product from Step B (0.343 g, 1.14 mmol) was dissolved in ethanol(10 mL) and sodium borohydride (50 mg, 1.32 mmol) was added in oneportion. The mixture was stirred at room temperature for 2 hours then asecond aliquot of sodium borohydride (50 mg, 1.32 mmol) was added. After30 minutes acetone was added to destroy excess reducing agent, thesolvent was evaporated to dryness, dilute sodium bicarbonate solutionwas added and the mixture extracted with dichloromethane (3×). Thecombined organic layers were dried over sodium sulfate and concentratedto dryness under vacuum to give a white solid. This was dissolved inanhydrous N,N-dimethylformamide (3 mL) andtert-butyldimethylchlorosilane (0.345 mg, 2.29 mmol) and imidazole(0.156 mg, 2.28 mmol) were added. The mixture was stirred at roomtemperature for 16 hours, diluted with water containing a littlehydrochloric acid to give an acidic solution and the mixture extractedwith dichloromethane (3×). The combined organic layers were dried oversodium sulfate and concentrated to dryness under vacuum. The residue waspurified by flash chromatography on a 40 g RediSep column (Teledyne IscoInc., Lincoln Nebr.) (eluted with 0-20% ethyl acetate in heptane) toyield the title compound as a colorless viscous oil (0.38 g). ¹H NMR(400 MHz, CDCl₃) δ 7.78 (br s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.51 (br d,J=8.3 Hz, 1H), 4.90(d, J=13.4 Hz, 1H), 4.76(d, J=13.4 Hz, 1H), 4.63(d,J=2.9 Hz, 1H), 1.96 (d, J=2.9 Hz, 1H), 1.68-1.08 (m, 10H), 0.95 (s, 9H),0.95 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H). MS (ES⁻) Calc: 416.59, Found:461.5 (M+HCO₂ ⁻).

Step D:(2-(methoxy(1-methylcyclohexyl)methyl)-5-(trifluoromethyl)phenyl)methanol

To a solution of the Step C product (0.38 g, 0.787 mmol) in anhydroustetrahydrofuran (3 mL) was added sodium hydride (60% dispersion inmineral oil, 47 mg, 1.18 mmol). The mixture was stirred at roomtemperature for 10 minutes then iodomethane (1.574 mmol, 0.097 mL) wasadded. After 60 hours the mixture was diluted with water and extractedwith heptane (3×). The combined organic layers were dried over sodiumsulfate, concentrated to dryness under vacuum, the residue dissolved intoluene and concentrated to dryness under high vacuum. The residue wasdissolved in anhydrous tetrahydrofuran (4 mL) under nitrogen and asolution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 1.5 mL,1.5 mmol) was added at room temperature. After 90 minutes the mixturewas diluted with water and extracted with dichloromethane (3×). Thecombined organic layers were dried over sodium sulfate, concentrated todryness under vacuum, the residue dissolved in xylenes and concentratedto dryness under high vacuum to give the title compound as an oil (0.218g) ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.55 (s, 1H), 7.55 (s, 1H),4.97 (dd, J=13.3, 5.4 Hz, 1H), 4.73 (dd, J=13.3, 3.5 Hz, 1H), 4.15 (s,1H), 3.15 (s, 3H), 1.78 (m, 1H), 1.68-1.21 (m, 8H), 1.2-1.02 (m, 2H),0.90 (s, 3H). MS (ES⁻) Calc: 316.17, Found: 361.3 (M+HCO₂ ⁻).

Step E:N-(2-(methoxy(1-methylcyclohexyl)methyl)-5-(trifluoromethyl)benzyl)-N-3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

To a mixture of the Step D product (210 mg, 0.665 mmol) andtetrabromomethane (231 mg, 0.7 mmol) in anhydrous dichloromethane (5 mL)under N2 at 0° C. was added powdered triphenylphosphine (192 mg, 0.73mmol). After 90 minutes further aliquots of tetrabromomethane (23 mg,0.07 mmol) and powdered triphenylphosphine (19 mg, 0.073 mmol) wereadded and the mixture stirred for 6 hours. The solvent was then removedunder vacuum and the residue was purified by flash chromatography on a12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with0-50% ethyl acetate in heptane) to give2-(bromomethyl)-1-(methoxy(1-methylcyclohexyl)methyl)-4-(trifluoromethyl)benzene(194 mg). ToN-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(Preparation 5, 216 mg, 0.66 mmol) was added sodium hydride (60%dispersion in mineral oil, 40 mg, 1 mmol), the air in the flask wasreplaced by nitrogen and anhydrous N,N-dimethylformamide (4 mL) wasadded. Hydrogen was evolved briskly and a yellow solution formed,darkening to orange-brown over 1 hour. A solution of2-(bromomethyl)-1-(methoxy(1-methylcyclohexyl)methyl)-4-(trifluoromethyl)benzene(194 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (2×1 mL) wasadded. The mixture was stirred at room temperature for 16 hours, dilutedwith water containing lithium chloride and a little hydrochloric acid togive an acidic solution and the mixture extracted with dichloromethane(3×). The combined organic layers were dried over sodium sulfate andconcentrated to dryness under vacuum. The residue was purified by flashchromatography on a 12 g RediSep column (Teledyne Isco Inc., LincolnNebr.) (eluted with 0-60% ethyl acetate in heptane) to yield the titlecompound as a colorless viscous oil (0.24 g). ¹H NMR (400 MHz, CDCl₃)δ7.79 (s, 1H), 7.65 (s, 2h), 7.65-7.51 (m, 2H), 7.37 (s, 1H), 5.06 (d,J=16 Hz, 1H), 4.79 (d, J=16.3 Hz, 1H), 4.61 (d, J=16.3 Hz, 1H),4.61-4.51 (m, 1H), 4.22 (s, 3H), 4.10 (s, 1H), 2.98 (s, 3H), 1.65-1.56(m, 1H), 1.56-1.18 (m, 7H), 1.17-0.98 (m, 2H), 0.88 (s, 3H).

MS (ES³⁰) Calc: 623.56, Found: 624.5 (M+H⁺).

EXAMPLE 70(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-cyclopentyl-1-methoxy-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5yl)-amine

Step A:1-(2-(((3,5-Bis(trifluoromethyl)benzyl)(2-methyl-2-H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl-2-cyclopentylethanone

(Cyclopentylmethyl) magnesium bromide was prepared by the reaction ofmagnesium mesh (2.61 mol, 63.5 mg) with (bromomethyl)cyclopentane (2.61mmol, 426 mg, added portionwise until the reaction initiated) in diethylether (1 mL). This solution was added by syringe to a solution of2-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazole-5-yl)amino)methyl)-4-(trifluoromethyl)benzonitrile(0.653 mmol, 332 mg) in toluene (10 mL) contained in a Smith microwavevial under nitrogen. The microwave vial was heated at 65° C. in aBiotage microwave for 45 minutes. The mixture was poured into 25 mL of 2N hydrochloric acid and 50 mL of ethyl acetate and stirred at roomtemperature for 16 hours. The aqueous layer was extracted with ethylacetate (2×25 mL), the combined organic layer was dried with anhydroussodium sulfate and concentrated under reduced pressure to give a yellowoil (160 mg). The residue was purified by flash chromatography on a 12 gRediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 0-50%ethyl acetate in heptane) to yield the title compound as a yellow oil(0.185 gm, 48%). ¹H NMR (400 MHz, CDCl₃) δ7.69 (s, 1H) 7.67 (d, J=7.5Hz, 1H) 7.62 (s, 2H) 7.54 (d, J=7.8 Hz 1H) 7.52 (s, 1H) 4.89 (s, 2H)4.78 (s, 2H) 4.14 (s, 3H) 2.86 (d, J=7.1 Hz, 2H) 2.25-2.21 (m, 1H)1.82-1.76 (m, 2H) 1.6-1.57 (m, 2H) 1.31-1.30 (m, 2H) 1.1-1.03 (m, 2H).LC-MS calc. 593.4, found 594.5 (M+H)

Step B:1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-cyclopentylethanol

To a solution of1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2-H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl-2-cyclopentylethanone(123 mg, 0.207 mmol) in methanol (15 mL) was added sodium borohydride(7.8 mg, 0.207 mmol) at room temperature. After 1 hour the solvent wasremoved under reduced pressure, the residue dissolved in 20 mL of ethylacetate (20 mL) and washed with water (10 mL). The combined organicswere dried with anhydrous sodium sulfate and concentrated to drynessunder reduced pressure. The residue was dissolved in dichloromethane andpurified by flash chromatography on a 4 g RediSep column (Teledyne IscoInc., Lincoln Nebr.) (eluted with 0-60% ethyl acetate in heptane) toyield the title compound as a clear oil (0.025 gm). ¹H NMR (400 MHz,CDCl₃) δ 7.76 (s, 1H) 7.62 (s, 2H) 7.56(d, J=7.8 Hz, 1H) 7.34 (s, 1H)4.96-4.92 (m, 1H) 4.85 (s, 2H) 4.81 (q, J=15.3 Hz, J=16.1 Hz, 2H) 4.2(s, 3H) 1.9-1.4 (m, 11H).

LC-MS calc. 595.5, found 596.5 (M+H).

Step C:(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-cyclopentyl-1-methoxy-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-cyclopentylethanolwas converted to the methyl ether with methyl iodide using a procedureanalogous to that used for the preparation ofN-(2-(cyclohexyl(methoxy)methyl)-5-trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine.LC-MS Calc. 609.5, found 610.5 (M+H).Examples 71-73 were prepared by an analogous series of reactions from2-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazole-5-yl)amino)methyl)-4-(trifluoromethyl)benzonitrileusing the appropriate Grignard reagent and alkylating agent

MS Example MS Found # Chemical Name Structure Calc M + 1 71N-(2-(2-cyclopentyl-1- ethoxyethyl)-5- (trifluoromethyl)benzyl)- N-(3,5-bis(trifluoromethyl)benzyl)- 2-methyl-2H-tetrazol-5- amine

623.5 624.6  72* N-(2-(2-ethyl-1- methoxybutyl)-5-(trifluoromethyl)benzyl)- N-(3,5- bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5- amine

597.5 598.5 73 N-(2-(1-ethoxy-2- ethylbutyl)-5-(trifluoromethyl)benzyl)-N- (3,5- bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5- amine

611.5 612.5* For Example 72: ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 7.67 (s,2H), 7.57 (dd, J=1.24, 8.3 Hz, 1H), 7.53 (d, J=8.3, 1H), 7.38 (s, 1H),4.85 (d, J=16.18 Hz, 1H), 4.73 (d, J=16.18 Hz, 1H), 4.74 (s, 2H), 4.28(d, J=6.22, 1H), 4.22 (s, 3H), 3.08 (s, 3H), 1.5-1.34 (m, 3H), 1.23 (m,1H), 1.11 (m, 1H), 0.75 (t, J=7.47, 3H), 0.74 (t, J=7.47 Hz, 3H).

EXAMPLE 74N-(2-(1-Cyclopentyl-2-methoxypropan-2-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

Step A:2-(2-(((3,5-Bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-1-cyclopentylpropan-2-ol

To a solution of1,-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2-H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl-2-cyclopentylethanone(160 mg, 0.269 mmol) in anhydrous THF (10 mL) at 0° C. was addedmethylmagnesium bromide (3.0 M solution in THF, 0.359 mL, 1.07 mmol).After stirring for 30 minutes the solution was warmed to room temp andstirred for 1.5 hours. After 1.5 hours solution was portioned between 2N HCL (10 mL) and ethyl acetate (20 mL). The mixture was stirred at roomtemperature for 10 minutes before the layers were separated. The aqueouslayer was extracted with ethyl acetate (3×15 mL). The combined organicslayers were dried with anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to give a yellow oil. (160 mg, 97%).¹H NMR (400 MHz, CDCl₃) δ 7.72 (s, 1H) 7.67(s, 2H) 7.38 (m, 3H) 5.32 (d,J=16.6 Hz, 1H) 5.01 (d, J=16.6 Hz, 1H) 4.78 (s, 2H) 4.13 (s, 3H) 1.92(dd, J=5.4 Hz, J=5.4 Hz) 1.80 (dd, J=5.81 Hz, J=6.24 Hz) 1.64 (m, 2H)1.59 (s, 3H) 1.54 (m, 3H) 1.35 (m, 2H) 0.88 (m, 2H). LC-MS Calc. 609.5,found 610.5 (M+H).

Step B:N-(2-(1-Cyclopentyl-2-methoxypropan-2-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

To a solution ofN-(2-(1-cyclopentyl-2-methoxypropan-2-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(20 mg, 0.032 mmol) in anhydrous THF (3 mL) at room temperature wasadded sodium bishexamethyldisilylamide (1.0 M solution in THF, 0082mmol, 0.082 mL). After 10 minutes methyl iodide (0.164 mmol, 23 mg) wasadded and the solution was stirred at room temperature for 72 hours. Themixture was diluted with water, extracted with ethyl acetate (3×15 mL),the combined organic layers were dried with anhydrous sodium sulfate andconcentrated under reduced pressure to give a yellow oil (40 mg). Theresidue was purified by flash chromatography on a 4 g RediSep column(Teledyne Isco Inc., Lincoln Nebr.) (eluted with 0-40% ethyl acetate inheptane) to yield the title compound as a clear oil (0.015 gm, 73%). ¹HNMR (400 MHz, CDCl₃) δ 7.76 (s, 1H) 7.62 (s, 2H) 7.58 (s, 2H) 7.34 (s,1H) 4.8 (s, 2H) 4.71 (s, 2H) 4.34 (dd, J=3.5 Hz, J=9.1 Hz, 1H) 4.21 (s,3H) 3.1 (s, 3H) 1.91 (m, 1H) 1.75 (m, 2H) 1.52 (m, 4H) 1.21 (m, 2H) 1.0(m, 1H) 0.84 (m, 1H). LC-MS calc 623.5, found 624.5 (M+1).

EXAMPLE 75N-(2-(1-Cycloheptyl-1-methoxyethyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

This compound was prepared by an analogous series of reactions to thatused for the preparation ofN-(2-(1-cyclopentyl-2-methoxypropan-2-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-aminefrom2-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazole-5-yl)amino)methyl)-4-(trifluoromethyl)benzonitrileby the addition of cycloheptylmagnesium bromide followed bymethylmagnesium bromide then alkylation with methyl iodide LC-MS calc637.5, found 606 (M-OCH₃).

EXAMPLE 76N-(2-(1-Cyclohexyl-1-methoxypropyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

This compound was prepared by an analogous series of reactions to thatused for the preparation ofN-(2-(1-cyclopentyl-2-methoxypropan-2-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-aminefrom2-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazole-5-yl)amino)methyl)-4-(trifluoromethyl)benzonitrileby the addition of cyclohexylmagnesium bromide followed byethylmagnesium bromide then alkylation with methyl iodide. LC-MS calc637.5, found 638.5 (M+H).

Preparation 43: 4,4-Dimethylcyclohexanone

4,4-Dimethylcyclohexanone was prepared by a procedure similar to thatdescribed in patent ref: PCT Int. Appl. 2005005456 20, January 2005.4,4-Dimethylcyclohex-2-enone (3.5 g, 28.18 mmol) was dissolved in ethylacetate (50 mL). The solution was shaken for 45 minutes under anatmosphere of hydrogen (10 p.s.i.). The completion of the reaction wasestablished by GC-MS then the solution was filtered through a pad ofcelite and rinsed through with ethyl acetate. The solvent was removedunder reduced pressure to give a clear colorless oil which crystallizedon standing (3.45 gm, 97%). ¹H NMR (400 MHz, CDCl₃) δ 2.29 (m, 4H) 1.61(m, 4H) 1.04 (s, 6H). MS calc 126.5, found 127.1 (M+H).

Preparation 44:2-(Bromomethyl)-1-(1-methoxycyclopentyl)-4-(trifluoromethyl)benzene

To a solution of(2-(1-methoxycyclopentyl)-5-(trifluoromethyl)phenyl)methanol (10 mg,0.036 mmol) in anhydrous dichloromethane (5 mL) was added carbontetrabromide (14.5 mg, 0.043 mmol) followed by triphenylphosphine (11.47mg, 0.043 mmol). The mixture was stirred at room temperature for 72hours then the solvent was removed under reduced pressure. The residuewas diluted with dichloromethane and hexanes, placed on 1 g of silicagel (Bakerbond spe disposable extraction columns, Mallinkrodt Baker Inc.Phillipsburg, N.J.) and eluted with hexanes to give the title compound(12 mg, 97.6%). ¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H) 7.46 (d, J=9.1Hz, 1H) 7.40 (d, J=8.3 Hz, 1H) 4.97 (s, 2H) 2.94 (s, 3H) 2.30 (m, 2H)2.0 (m, 2H) 1.85 (m, 2H) 1.74 (m, 2H).

GC-MS (El) calc 337, found 337.

Preparation 45: 4-(2(Bromomethyl)-4-(trifluoromethyl)phenyl-4-methoxycyclohexanecarbonitrile

This compound was prepared from 4-cyanocyclohexanone and(2-bromo-5-(trifluoromethyl)benzyloxy) (tert-butyl) dimethylsilane in asequence of steps analogous to the preparation of tert-butyl4-(2-(bromomethyl)-4-trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate.

EXAMPLE 774-(2-(((3,5-Bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-4-methoxycyclohexanecarbonitrile

To a solution ofN-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazole-5-amine (285mg, 0.877 mmol) in anhydrous THF (5 mL) was added sodium hydride (60%dispersion in mineral oil, 105 mg, 2.63 mol) and the mixture was stirredfor 5 minutes then a solution of 4-(2(bromomethyl)-4-(trifluoromethyl)phenyl)-4-methoxycyclohexanecarbonitrile(330 mg, 0.877 mmol) in anhydrous THF (5 mL) was added. A furtheraliquot of sodium hydride (52 mg, 1.3 mmol) was added. The solution wasstirred at room temperature for 72 hours. Water and 2 N HCl (5 mL) wereadded and the mixture was extracted with ethyl acetate (3×20 mL). Thecombined organics were dried with anhydrous sodium sulfate andconcentrated under reduced pressure to give a yellow oil (0.65 gm). Thismaterial was initially purified by flash chromatography on a 40 gRediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-75%ethyl acetate in heptane) and finally purified on 1 mm silica gel rotor(Chromatotron, Harrison Research) (eluted with 20-70% dichloromethane inheptane) to yield the title compound as a colorless foam (134 mg,24.6%). ¹H NMR (400 MHz, CDCl₃) δ 7.74 (s, H) 7.67(s, 2H) 7.44 (d,J=5.81 Hz, 2H) 7.29 (d, J=8.72 Hz, 1H) 5.01 (s, 2H) 4.76 (s, 2H) 4.15(s, 3H) 2.87(s, 3H) 2.43(m, 1H) 2.20(d, J=12.45 Hz, 2H) 1.99(m, 2H)1.55(m, 4H). LC-MS calc. 620, found 621.5 (M+H)

EXAMPLE 78N-(2-(1-methoxycyclopentyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

The title compound was prepared from2-(bromomethyl)-1-(1-methoxycyclopentyl)-4-(trifluoromethyl) benzene ina analogous manner to that described above. LC-MS (ES+) calc. 581.4,found 582.4 (M+H).Examples 79-30 were prepared by an analogous sequence of reactionsstarting from(2-bromo-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane and theappropriate cyclic ketone.

MS Example MS Found # Chemical Name Structure Calc M + 1 79N-(2-(1-methoxy-4,4- dimethylcyclohexyl)-5- (trifluoromethyl)benzyl)-N-(3,5- bis(trifluoromethyl)benzyl)- 2-methyl-2H-tetrazol-5- amine

623.5 624.5 80 methyl 4-(2-(((3,5- bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5- yl)amino)methyl)-4- (trifluoromethyl)phenyl)-4-methoxycyclohexanecarboxylate

653.5 654.5

Preparation 46:N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-(2-(tert-butyldimethylsilyloxy)ethyl)-2H-tetrazol-5-amine

To a solution ofN-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine(51 mg; 0.086 mmol) in 2-methyltetrahydrofuran (1.0 mL) was added sodiumcarbonate (38 mg; 0.358 mmol), N,N-dimethylformamide (0.4 mL) and(2-bromoethoxy)-tert-butyldimethylsilane (100 mg; 0.418 mmol). Reactionwas stirred for 16 hours at 60° C. The reaction was diluted with ethylacetate, washed twice with water and then brine. The organic was driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with5-35% ethyl acetate in heptane) to give 45 mg (70% yield) of a colorlessgum. ¹H NMR (400 MHz CDCl₃) δ ppm 7.77 (s, 1H), 7.73 (s, 2H), 7.47 (d,J=9.96 Hz, 2H), 7.41 (d, J=8.30 Hz, 1H), 5.11 (s, 2H), 4.80 (s, 2H),4.55 (t, J=5.39 Hz 2H), 4.08 (t, J=5.39 Hz, 2H), 2.94 (s, 3H), 2.12 (m,2H), 1.98 (m, 2H), 1.8-1.45 (m, 8H), 0.82 (s, 9H), −0.07 (s, 6H).

EXAMPLE 812-(5-((2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)benzyl)amino)-2H-tetrazol-2-yl)ethanol

To a solution ofN-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-(2-(tert-butyldimethylsilyloxy)ethyl)-2H-tetrazol-5-amine(42 mg, 0.056 mmol) in 2-methyltetrahydrofuran (1.5 mL) was addedtetrabutylammonium fluoride (0.1 mL; 0.1 mmol; 1.0M in tetrahydrofuran).Reaction was stirred at room temperature for 1.5 hours. The reaction wasconcentrated in vacuo. The residue was purified by 4 g RediSep column(Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-40% ethyl acetate inheptane) to give 34 mg (95% yield) of a gum. MS (ES+): Calc: 639.5,Found: 640.5 (M+H). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.78 (s, 1H), 7.74 (s,2H), 7.45 (m, 3H), 5.10 (s, 2H), 4.81 (s, 2H), 4.61 (t, J=4.98 Hz, 2H),4.11 (q, J=6.22, 5.8 Hz 1, 2H), 2.94 (s, 3H), 2.44 (t, J=6.64, 6.22 Hz,1H), 2.11 (m, 2H), 2.19 (m, 2H), 1.82-1.45(m, 8H).

Preparation 47:(3,5-Bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine

Step A: Preparation of 2: 2-Bromo-5-trifluoromethyl-benzylaminemethanesulfonic acid salt

Sodium borohydride (NaBH₄) (225 g, 5.96 mol) was charged to a 22 L flaskfollowed by THF (6.8 L, anhyd). The mixture was cooled in an ice-waterbath. Trifluoroacetic acid (TFA) (518 ml) was added to THF (1.4 L) andthis solution was also cooled in an ice-water bath. The TFA solution wasadded to the NaBH₄ suspension over 2.5 hours. The ice-water bath wasremoved and the resulting mixture was stirred at ambient temperature for2 hours. 2-Bromo-5-trifluoromethyl-benzonitrile (678 g, 2.71 mol) wasdissolved in THF (1.2 L). The TFA/NaBH₄ mixture was again cooled in anice-water bath and the nitrile solution was added over 1.5 hours. Themixture was allowed to reach ambient temperature while stirring for 16hours. LC analysis of an aliquot revealed complete reaction. The mixturewas cooled in an ice bath and methanol (2 L) was added over 1 hour.Volatiles were removed in vacuo and ethylacetate (4 L) was added. Thismixture was washed with water (3 L) containing sodium-potassiumtartarate (1 Kg). The aqueous layer was washed with ethylacetate (2 L)and the combined organics were washed with brine (2 L), dried oversodium sulfate, filtered, and concentrated. The residue was dissolved inTHF (3 L) and cooled in an icewater bath. Methanesulfonic acid (195 ml)was added and the mixture was stirred for 2 hours. The resulting solidwas filtered and dried in vacuo (676 g, 71% yield). ¹H-NMR (CD₃OD) δ7.92 (d, 8.3 Hz, 1H), 7.87 (s, 1H), 7.65 (d, 8.3 Hz, 1H), 4.34 (s, 2H),2.66 (s, 3H). Mass Spec (ESI): M+1=255.9

Step B: Preparation of(3,5-Bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-amine

To the product from step A (640 g in methyl-tert-butyl-ether (4.3 L) wasadded 1N sodium hydroxide (3.4 L). The mixture was stirred until 2 clearlayers formed. The organics were washed with brine, dried over sodiumsulfate, filtered, and concentrated to the free amine (460 g). The freeamine (460 g, 1.81 mol) was taken into 1,1-dichloroethene (4.3 L) and3,5-bis(trifluoromethyl)benzaldehyde (438 g, 1.81 mol) was added. Themixture was cooled in an ice-water bath and NaBH(CH₃CO₂)₃ (767 g, 3.62mol) was added. The mixture was stirred for 16 hours at which point LCanalysis revealed complete reaction. Saturated aq potassium carbonatewas added until pH 8 was reached. Added water (1 L) and filteredundissolved salts. The layers were separated and the aqueous layer waswashed with 1,1-dichloroethene (2 L). The combined organics were washedwith brine, dried over sodium sulfate, filtered, and concentrated (880 gproduct, >95% yield). ¹H-NMR of HCl salt (CD₃OD) δ 8.23 (s, 2H), 8.09(s, 1H), 7.98 (s, 1H), 7.93 (d, 8.3 Hz, 1H), 7.67 (d, 8.3 Hz, 1H) 4.61(s, 2H), 4.56 (s, 2H). Mass Spec (ESI): M+1=480.1

Step C: Preparation of(2-bromo-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)benzyl)cyanamide

To the product of step B (873 g, 1.82 mol) in ethanol (4.6 L) was addedsodium acetate (452 g, 5.46 mol). The resulting mixture was stirred for20 minutes and then cyanogen bromide (386 g, 3.64 mol) was added. Thismixture was stirred for 2 hours at which point the reaction was completeas evidenced by LC analysis. Water (4 L) was added and volatiles wereremoved in vacuo. Toluene (4 L) was added and the mixture was stirreduntil 2 clear layers formed. The layers were separated and the aqueouslayer was washed with toluene (2 L). The combined organics were washedwith brine (1 L), dried over sodium sulfate, filtered, and concentrated(910 g yield). ¹H-NMR (CDCl₃) δ 7.83 (s, 1H), 7.71 (m, 3H), 7.54 (d, 1.7Hz, 1H), 7.46 (dd, 2.1 Hz, 8.3 Hz, 1H), 4.38 (s, 2H), 4.34 (s, 2H). MassSpec (ESI): M+1=505.0

Step D: Preparation ofN-(2-bromo-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine

To the product of step C (909 g, 1.80 mol) in methyl tert-butyl ether (9L) was added triethylamine (2.5 L, 18 mol) followed bytrimethylsilylazide (415 g, 3.60 mol). The resulting mixture was heatedto 50° C. for 8 hours. An aliquot was checked by HPLC and startingmaterial was still present. The mixture was cooled andtrimethylsilylazide (50 g) was added. The mixture was again heated to50° C. and stirred 3 hours. After cooling, 1N sodium hydroxide (9 L) wasadded. The layers were separated (added 150 ml ethanol to facilitateseparation). The organics were washed with aqueous 10% citric acidsolution (8 L, then 2 L) until washings were acidic. The organics weredried over sodium sulfate, filtered, and concentrated. The resultingsolid turned white upon standing (976 g, 99% yield). ¹H-NMR (CD₃OD) δ7.47 (m, 3H), 7.64 (d, 8.3 Hz, 1H), 7.44 (d, 2.1 Hz, 1H), 7.38 (dd, 2.1Hz, 8.3 Hz, 1H), 4.88 (s, 2H), 4.86 (s, 2H). Mass Spec (ESI): M+1=548.0

Step E: Preparation ofN-(2-bromo-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

To the product of step D (500 g, 0.912 mol) in 2-methyl THF (9 L) wasadded sodium carbonate (386 g, 3.65 mol), dimethylformamide (4 L), anddimethyl sulfate (156 ml, 1.7 eq). The resulting mixture was heated to50° C. for 16 hours at which point LC analysis revealed completion.After cooling, water (9 L) was added and the layers were separated. Theorganic layer was washed with concentrated ammonium hydroxide (6.5 L).Brine was added to facilitate layer separation. The organic layer wasdried over sodium sulfate, filtered, and concentrated. The residue washeated in hexanes and filtered hot to obtain a white solid (229 g). Themother liquor was combined with the mother liquor from another batch(460 g tetrazole) and purified on a Biotage® 150M system (Uppsala,Sweden) (eluted with 5-10% ethyl acetate in hexanes). The title compoundwas isolated as a white solid (729 g, 74% yield). ¹H-NMR (CDCl₃) δ 7.71(s, 1H), 7.62 (m, 3H), 7.41 (d, 1.7 Hz, 1H), 7.34 (dd, 2.1 Hz, 8.3 Hz,1H), 4.80 (s, 2H), 4.78 (s, 2H), 4.18 (s, 3H). Mass Spec (ESI):M+1=562.0

Preparation 48:(3,5-Bis-trifluoromethyl-benzyl)-(2-chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine

Step A:N-(3,5-bis(trifluoromethyl)benzylidene)(2-chloro-5-(trifluoromethyl)phenyl)methanamine

To a 100 mL round bottom flask, equipped with a Dean Start Trap wascharged 50 mL of toluene, 5.0 gm of 2-chloro-5-trifluoromethyl benzylamine and 5.8 gm of 3,5-bis(trifluoromethyl)benzaldehyde and 50 mg ofpara-toluenesulfonamide. The reaction was heated until water no longerdistilled off about 3 hours, then cooled to ambient temperature and thesolvent removed in vacuum. The crude product was used directly in thenext step without further purification. 10.0 gm.

Step B:N-(2-chloro-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)phenyl)methanamine

To a solution of the compound from step A in ethanol was added 4 gm ofsodium borohydride and the reaction was allowed to stir overnight atambient temperature. The reaction was quenched with 50 mL of methanoldiluted with 100 mL of water and 100 mL of methyl tert-butyl ether. Thelayers were separated and the organic layer dried over magnesiumsulfate, filtered and concentrated to an oil. 10 gm of desired amine wascollected which was used in the next step without further purification.¹H NMR (400 MHz, CDCl₃) 7.84 (s, 2H), 7.77 (s, 1H), 7.66 (s, 1H), 7.48(s, 2H), 7.47 (s, 4H), ¹³C NMR (400 MHz, CDCl₃) δ 142.6, 183.3, 130.4,128.4, 127.1, 127.0, 125.6, 121.4, 52.4.

Step C:(2-chloro-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)benzyl)cyanamide

To the mixture of the compound from Step B (10 gm), 5.6 gm of sodiumacetate 100 mL of ethanol was added over 15 minutes 15.5 mL of cyanogenbromide 3M in dichloromethane. The reaction mixture was stirred atambient temperature until reaction completion. When the reaction wasjudged complete, it was diluted with 200 mL of toluene and 200 mL ofsodium hydroxide. The layers were separated and the organic layer driedwith magnesium sulfate, filtered and concentrated to an oil. 7.8 gm (74%yield). The product was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) 7.84 (s, 2H), 7.56 (s, 3H), 7.66(m, 4H), 7.48 (s, 2H), 4.39 (s, 2H), 4.36 (s, 2H)

Step D:N-(2-chloro-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-1H-tetrazol-5-amine

A solution of 5 gm of the compound from Step C, 50 mL of 2-methyl THF 5mL, triethanolamine and 2.5 mL of trimethyl silyl azide was heated at50° C. until reaction completion. When the reaction was judged complete,the reaction mixture was cooled and 50 mL of 1 N sodium hydroxide added,The layers were separated and the organic layer washed with 50 mL of 10%citric acid. The organic layer was concentrated and triturated withhexane to yield 4.6 of the desired compound. 85% yield. ¹H NMR (400 MHz,CDCl₃) 7.84 (s, 2H), 7.74 (m, 3H), 4.90 (s, 4H)C, H, N, Calculated,(found) 42.92 (42.98), 2.20 (1.97), 13.90 (13.54)

Step E:N-(2-chloro-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

To a suspension of the compound from step D 2.5 gm, 2.0 gm of sodiumcarbonate, 50 mL of 2-methyl THF and 2.5 mL of DMF was added 1.0 gm ofdimethyl sulfate. The reaction mixture was heated at 40° C. untilreaction was judged complete. When the reaction was judged complete thereaction mixture was cooled to room temperature and 12.4 mL of 5%ammonium hydroxide added. The mixture was allowed to stir for 30 minutesat ambient temperature. The organic layer was removed, dried overmagnesium sulfate, filtered and concentrated to an oil to recover 2.2 gmof the desired methylated tetrazole. 88% yield. ¹H NMR (400 MHz, CDCl₃)7.70 (s, 1H), 7.64 (s, 2H), 7.25 (s, 1H), 7.24 (2, 2H), 4.21, (s, 2H),4.20 (s, 2H). C, H, N Calculated (found) 44.07 (44.10) 2.53 (2.13),13.53 (13.41)

Preparation 49: 5-Amino-2-methyl 2H-tetrazole

Step A: Dibenzylcyanamide

To a dry 2 L round bottom flask, equipped with an overhead stirrer,charged: sodium acetate (120 gm), 1 dibenzyl amine (100 gm) and 600 mLof ethanol. To this suspension at room temperature, was added a 3 Msolution of cyanogen bromide in methylene chloride over 30 minutes (340mL). The suspension was allowed to stir at ambient temperature untilreaction completion was observed via HPLC. The reaction mixture wasdiluted with 1 L of toluene and 1 N sodium hydroxide was added over 15minutes. The reaction mixture was stirred for 1 hour and the layersseparated. The organic layer was dried over sodium sulfate, filtered,and concentrated to an oil that solidified upon standing.Recrystallization from a 1:1 2 L mixture of IPE/Heptanes gave 101 g(89%) of product. ¹H NMR (400 MHz, CD₃OD) 7.42-7.15 (m, 10H), 1.31 (s,4H). ¹³C NMR (400 MHz, CD₃OD) δ 135.1, 128.8, 128.7, 128.5, 118.0, 54.6.C, H, N Calculated (found) 81.05 (80.71), 6.35 (6.52), 12.60 (12.65)

Step B: N,N-dibenzyl-1H-tetrazol-5-amine

Product from step A (50 g) was dissolved in 500 mL of toluene and 150 mLof triethyl amine and trimethyl silyl azide (60 mL) were added dropwiseover 15 minutes. The reaction mixture was heated to 50° C. and held atthis temperature until the reaction was complete as noted by HPLC. Aftercooling to room temperature, 500 mL of 1 M sodium hydroxide and 500 mLof methylene chloride were added. The biphasic solution was stirred for1 hour and the layers separated. The lower organic layer wasconcentrated and redissolved in ethyl acetate. The ethyl acetate layerwas then treated with 200 mL of 10% citric acid and stirred for 30-60minutes. The layers were separated and the product layer was dried oversodium sulfate, filtered, and concentrated to an oil. The oil wascrystallized from IPE to give 46 gm, (77%) of product. ¹H NMR (400 MHz,CDCl₃) 7.38-7.24 (m, 10H), 4.60 (s, 4H). ¹³C NMR (400 MHz, CDCl₃) δ159.2, 136.3, 129.1, 128.4, 55.0. C, H, N Calculated (found) 67.90(67.73), 5.70 (5.53), 26.40 (26.01)

Step C: N,N-dibenzyl-2-methyl-2H-tetrazol-5-amine

Product from Step B (25 g) was dissolved in 250 mL of 2-methyl THF and25 mL of DMF. To this was added sodium carbonate (40 gm) and dimethylsulfate (18 mL) over 15 minutes. The reaction mixture was heated to 45°C. and held at this temperature until the reaction was complete as notedby HPLC. After cooling to room temperature, 250 mL of 5% ammoniumchloride was added and the biphasic solution was allowed to stir for atleast 30 minutes. The layers were then separated, dried over sodiumsulfate, filtered, and concentrated to an oil. (26 gm) HPLC analysis ofthe oil showed a 9:1 mixture of 2-methyl to 1-methyl regioisomers. Thetwo isomers were separated by flash chromatography, eluting with 9:1Hexane/EtOAc, to provide 21.2 gm (77%) of the desired 2-methylderivative, N,N-dibenzyl-2-methyl-2H-tetrazol-5-amine. ¹H NMR (400 MHz,CDCl3) 7.34-7.22 (m, 10H), 4.61 (s, 4H). ¹³C NMR (400 MHz, CDCl₃) δ159.2, 136.3, 129.1, 128.4, 55.0 ¹H NMR (400 MHz, CDCl3) 7.34-7.22 (m,10H), 4.63 (s, 4H), 4.15 (s, 3H) ¹³C NMR (400 MHz, CDCl₃) δ 170, 137.6,128.7, 128.2, 127.6, 51.3, 39.6 and 1.6 g (10%) of the 1-methylderivative N,N-Dibenzyl-1-methyl-1H-tetrazol-5-amine. Recrystallizationby slow evaporation from diethyl ether provided good X-ray qualitycrystals. ¹H NMR (400 MHz, CDCl₃) 7.34-7.22 (m, 10H), 4.47 (s, 4H), 3.74(s 3H) ¹³C NMR (400 MHz, CDCl₃) δ 159.2, 136.3, 129.1, 128.4, 55.0

Step D: 2-methyl-2H-tetrazol-5-amine

To a clean stainless steel reactor added palladium hydroxide (1 g), 10gm of N,N-dibenzyl-2-methyl-2H-tetrazol-5-amine from Step C (10 g) andethanol (100 mL). The reaction was charged with hydrogen and heated to50° C. and the pressure was maintained at 50 psi hydrogen for 16 hours.When the uptake of hydrogen had ceased, the reaction was purged withnitrogen and the catalyst removed by filtration. The pad was washed with25 mL of ethanol and combined with the filtrate and concentrated to anoff white solid to give 2.7 gm (73%) of product. An analytical samplewas prepared by recrystallization from isopropanol. ¹H NMR (400 MHz,DMSO-d₆) 5.94 (s 2H), 4.03 (s 3H) ¹³C NMR (400 MHz, DMSO-d₆ δ 167.8,40.52, C, H, N Calculated (found) 68.79 (68.54), 6.13 (6.41), 25.07(24.83)

Alternatively, employing a mixture of regioisomers: to a clean stainlesssteel reactor added palladium hydroxide (1.4 g), 14 g of a 9:1 mixtureof N,N-dibenzyl-2-methyl-2H-tetrazol-5-amine andN,N-Dibenzyl-1-methyl-1H-tetrazol-5-amine from Step C, and ethanol (140mL). The reaction was charged with hydrogen and heated to 50° C. and thepressure was maintained at 50 psi hydrogen for 16 hours. When the uptakeof hydrogen ceased the reaction was purged with nitrogen and thecatalyst removed via filtration. The pad was washed with 50 mL ofethanol and combined with the filtrate and concentrated to an off whitesolid to give 5.1 gm (quantitative mixture of1-methyl-2H-tetrazol-5-amine and 2-methyl-2H-tetrazol-5-amine). Thecrude reaction mixture was taken up in methylene chloride and theundesired isomer filtered away. The methylene chloride layer wasdisplaced with isopropanol to give 3.8 gm of the desired product.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application for all purposes.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

1. A compound selected from the group consisting of:(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(3,5-Bis-trifluoromethyl-benzyl)-{2-[methoxy-(1-methyl-piperidin-4-yl)-methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-(3,5-Bis-trifluoromethyl-benzyl)-{2-[methoxy-(1-methyl-piperidin-4-yl)-methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine;(S)-(3,5-Bis-trifluoromethyl-benzyl)-{2-[methoxy-(1-methyl-piperidin-4-yl)-methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine;(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-methoxy-propyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-methoxy-propyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-methoxy-propyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;[2-(1-Benzyloxy-propyl)-5-trifluoromethyl-benzyl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-[2-(1-Benzyloxy-propyl)-5-trifluoromethyl-benzyl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine;(S)-[2-(1-Benzyloxy-propyl)-5-trifluoromethyl-benzyl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine;(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(3,5-Bis-trifluoromethyl-benzyl)-[2-(methoxy-phenyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(methoxy-phenyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(methoxy-phenyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-methoxy-2-phenyl-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-methoxy-2-phenyl-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-methoxy-2-phenyl-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-ethoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-ethoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-ethoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropyl-ethoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropyl-ethoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropyl-ethoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;(R)—N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;(S)—N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;N-(2-(1-cyclohexyl-1-methoxyethyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;(R)—N-(2-(1-cyclohexyl-1-methoxyethyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;(S)—N-(2-(1-cyclohexyl-1-methoxyethyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;(3,5-Bis-trifluoromethyl-benzyl)-{2-[methoxy-(tetrahydro-pyran-4-yl)-methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-(3,5-Bis-trifluoromethyl-benzyl)-{2-[methoxy-(tetrahydro-pyran-4-yl)-methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine;(S)-(3,5-Bis-trifluoromethyl-benzyl)-{2-[methoxy-(tetrahydro-pyran-4-yl)-methyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine;(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-methoxy-propyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;(R)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-methoxy-propyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;and(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-methoxy-propyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine;or a pharmaceutically acceptable salt of said compound.
 2. Apharmaceutical composition which comprises a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltof said compound and a pharmaceutically acceptable vehicle, diluent orcarrier.
 3. A pharmaceutical combination composition comprising: atherapeutically effective amount of a composition comprising a firstcompound, said first compound being a compound of claim 1, or apharmaceutically acceptable salt of said compound; a second compound,said second compound being an HMG CoA reductase inhibitor, an MTP/Apo Bsecretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, acholesterol absorption inhibitor, a cholesterol synthesis inhibitor, afibrate, niacin, a combination of niacin and lovastatin, a combinationof niacin and simvastatin, a combination of niacin and atorvastatin, acombination of amlodipine and atorvastatin, an ion-exchange resin, anantioxidant, an ACAT inhibitor or a bile acid sequestrant; and apharmaceutical vehicle, diluent or carrier.
 4. A pharmaceuticalcombination composition according to claim 3 wherein the second compoundis an HMG-CoA reductase inhibitor, a PPAR modulator, or niacin.
 5. Apharmaceutical combination composition according to claim 4 wherein thesecond compound is fenofibrate, gemfibrozil, lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin orpitavastatin.